Abstract
BackgroundTherapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies. A broader use of Id-based vaccination, however, is hampered by the complexity and costs due to the individualized production of protein vaccines. These limitations may be overcome by targeted DNA vaccines encoding stereotyped immunoglobulin V regions of B cell malignancies. We have here investigated whether such vaccines might elicit cross-reactive immune responses thus offering the possibility to immunize subsets of patients with the same vaccine.MethodsFusion vaccines targeting patient Id to mouse Major Histocompatibility Complex (MHC) class II molecules (chimeric mouse/human) or chemokine receptors (fully human) on antigen-presenting cells (APC) were genetically constructed for two Chronic Lymphocytic Leukemia (CLL) patients and one prototypic stereotyped B-cell receptor (BCR) commonly expressed by Hepatitis C Virus (HCV)-associated Non Hodgkin Lymphoma (NHL). The A20 murine B lymphoma cells were engineered to express prototypic HCV-associated B cell lymphoma BCR. Anti-Id antibody responses were studied against stereotyped and non-stereotyped BCRs on CLL patients’ cells as well as transfected A20 cells.ResultsDNA vaccination of mice with Id vaccines that target APC elicited increased amounts of antibodies specific for the patient’s Id as compared with non targeted control vaccines. Anti–Id antibodies cross-reacted between CLL cells with closely related BCR. A20 cells engineered to express patients’ V regions were not tumorigenic in mice, preventing tumor challenge experiments.ConclusionsThese findings provide experimental support for use of APC-targeted fusion Id DNA vaccines for the treatment of B cell lymphoma and CLL that express stereotyped BCRs.
Highlights
Therapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies
The dimerization unit consists of a shortened hinge region from hIgG3 whereas the N-terminal targeting unit can consist of either single chain fragment variable specific for surface molecules on antigen-presenting cells (APC) such as mouse Major Histocompatibility Complex (MHC) class II [10], mouse CD40 [13], human TLR2 and CD14 [14], or natural ligands such as the mouse chemokines CCL3 and CCL5 [15] and human CCL3 [16]
The CLLspecific V regions were identified in each case as identical VDJH and VJL sequences repeatedly obtained after cloning of PCR products
Summary
Therapeutic idiotypic (Id) vaccination is an experimental treatment for selected B cell malignancies. A broader use of Id-based vaccination, is hampered by the complexity and costs due to the individualized production of protein vaccines These limitations may be overcome by targeted DNA vaccines encoding stereotyped immunoglobulin V regions of B cell malignancies. Because of the very nature of the antigen (Ag) (i.e., Id), large scale clinical application of protein Id vaccination is limited by the need to prepare a custom-made vaccine for each and every patient. The poor immunogenicity of DNA vaccination can be improved by several means such as improved vector design and efficient electroporation [5] Another strategy is based on the finding that targeting of Ag to antigen-presenting cells (APC) enhances immunogenicity, as shown for chemical antibody (Ab)-Ag conjugates [6,7] and Ab-Ag fusion proteins [8,9]. Translational endeavour, the first fully murine Vaccibodies [10] have been extended to chimeric murine/human Vaccibodies, including tailormade Vaccibodies for multiple myeloma patients [17]
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