Delivery of Antigen to CD40 Induces Protective Immune Responses against Tumors

Abstract

Ligation of CD40 induces maturation of dendritic cells (DC) and could be a useful target for vaccines. In this study, we have constructed two types of Ab-based vaccine constructs that target mouse CD40. One type is a recombinant Ab with V regions specific for CD40 and has defined T cell epitopes inserted into its C region. The other type is a homodimer, each chain of which is composed of a targeting unit (single-chain fragment variable targeting CD40), a dimerization motif, and an antigenic unit. Such proteins bound CD40, stimulated maturation of DC, and enhanced primary and memory T cell responses. When delivered i.m. as naked DNA followed by electroporation, the vaccines induced T cell responses against MHC class II-restricted epitopes, Ab responses, and protection in two tumor models (myeloma and lymphoma). Two factors apparently contributed to these results: 1) agonistic ligation of CD40 and induction of DC maturation, and 2) delivery of Ag to APC and presentation on MHC class II molecules. These results highlight the importance of agonistic targeting of Ag to CD40 for induction of long-lasting and protective immune responses.

The Magnitude and IgG Subclass of Antibodies Elicited by Targeted DNA Vaccines Are Influenced by Specificity for APC Surface Molecules

“…One such Ab-enhancing format combines DNA vaccination with targeting of Ag to APC. This is achieved by the construction of DNA plasmids encoding secreted fusion proteins that target APC for increased delivery of Ag, resulting in improved immune responses (6)(7)(8)(9). In this study this principle is called a targeted DNA vaccine.…”

“…Targeted DNA vaccibody vaccines have previously been constructed with different APC-specific units such as single-chain fragment variable (scFv) specific for MHC class II (MHCII) (8,13) or CD40 (9), or chemokines such as MIP-1a (11,18) or Xcl1 (19). These targeted DNA vaccines have resulted in different levels of Abs (besides inducing T cells).…”

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

“…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). Although the APC-targeted vaccines have mostly been delivered as proteins (5)(6)(7)(8)(9)(10)(11)(12)(13), the principle has also been demonstrated for DNA vaccines (12,(14)(15)(16)(17).…”

“…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).…”

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].…”