DNA Vaccines Increase Immunogenicity of Idiotypic Tumor Antigen by Targeting Novel Fusion Proteins to Antigen-Presenting Cells

Abstract

Naked DNA vaccines have a number of advantages over conventional vaccines, but induce only weak immune responses. We have here investigated if this inadequacy may be overcome by inducing muscle to secrete fusion proteins with the ability to target antigen-presenting cells (APC). The novel targeted vaccines are homodimers with (i) two identical single-chain fragment variable (scFv) targeting units specific for MHC class II molecules on mouse APC, (ii) a human Ig hinge and C(H)3 dimerization unit, and (iii) two identical scFv tumor antigenic units (idiotypes) from B cell cancers. After plasmid injection and electroporation of mouse muscle, secreted vaccine proteins (vaccibodies) delivered idiotypic tumor antigen to APC in draining lymph nodes for induction of T and B cell responses that protected mice against tumor challenges with a multiple myeloma (MOPC315) and a B cell lymphoma (A20). Targeting to APC was essential for these effects. The results show that immunogenicity of plasmid DNA vaccines can be increased by inducing muscle to secrete proteins that target antigen to APC.

Simultaneous Targeting of Multiple Hemagglutinins to APCs for Induction of Broad Immunity against Influenza

“…, and A/black-headed gull/Netherlands/1/00 (H13N8)] were inserted separately as antigenic units into plasmids encoding an MHCII-targeted DNA vaccine format (16,18). Each plasmid encodes, under the same promoter, a targeting unit (scFv) that directs the vaccine toward MHCII molecules, a dimerization unit derived from the hinge and C H 3 exons of human IgG3, and one of the six HAs as an antigenic unit.…”

“…Vaccine plasmids were constructed as previously described, with Ag linked to an MHCII-specific scFv via a dimerization unit containing the C H 3 domain of human IgG3 (16,18). Briefly, HAs from A/Hong Kong/483/97 (H5N1), A/northern shoveler/California/HKWF115/07 (H6N1), A/pintail duck/Alberta/ 114/1979 (H8N4), A/Hong Kong/1073/99 (H9N2), A/duck/Yangzhou/906/ 2002 (H11N2), and A/black-headed gull/Netherlands/1/00 (H13N8) were picked up by PCR from cDNA (VG11689-C, VG11723-C, VG11722-C, VG11229-C, VG11705-C, and VG11721-C, all from Sino Biological, Beijing, China) and cloned into SfiI sites in the CMV-based pLNOH2 vector (29).…”

“…This could be chemokines that attract and activate leukocytes at the site of vaccine delivery (14) or perforin, which induces necrotic death (15). In another strategy, DNA has been constructed so that it encodes secreted fusion proteins that target Ags to APCs for enhanced immune responses (16)(17)(18)(19)(20)(21). This approach combines the attractiveness of DNA immunization with the well-known principle of APC targeting of Ag to increase Ag immunogenicity (22)(23)(24).…”

“…The increased efficacy conferred by MHCII targeting of Ag has recently been translated to influenza vaccination of ferrets and pigs (21). As a mechanism for enhanced Ab induction, it has been suggested that the DNA-encoded anti-MHCII-HA vaccine proteins bridge B cells and APCs in an APC-B cell synapse (16,27,28). In this article, we show that the same MHCII-targeted DNA vaccine format can induce strong Ab responses against H5, H6, H8, H9, H11, and H13 subtypes of group 1 influenza viruses.…”

Cellular immunotherapy in multiple myeloma: Lessons from preclinical models

“…The fusion proteins, called vaccibodies, consist in the variable fragment of an Id single chain (the tumor antigen) and a targeting moiety directed towards antigen-presenting cells (APC), for example the single chain variable fragment of APC-specific antibodies (anti-MHC II, anti-CD40) or chemokines (MIP1α, RANTES) [131][132][133][134]. Structural modifications to vaccibodies, like the generation of bivalent vaccines and the introduction of xenogeneic sequences, further enhanced the effectiveness of the chemokine-Id DNA vaccines [134].…”