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

Division of Oncology, Department of Medicine, Stanford University Medical Center, and Departments of Chemical Engineering and Bioengineering, Stanford University, Stanford, CA 94305.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2012; 109(36):14526-31. DOI: 10.1073/pnas.1211018109
Source: PubMed


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.

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    • "T and B cells from adaptive immunity have been shown to play key roles in tumor immunity; these cells can be engaged to prevent and control tumorogenesis [43] [44] [45] [46] [47]. Although, antibodies against tumor antigens and immune-modulatory molecules have been shown to be helpful in tumor treatment [43] [48] [49], T cells are often involved in this process and have been shown to play significant roles in the control of proliferative malignant cells [48] [49] [50] [51]. T cells recognize cognate antigens as small peptides bound to self-MHC molecules (pMHC complexes, Figure 1) [13, 15–19, 52, 53]. "
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    ABSTRACT: To circumvent pathology caused by infectious microbes and tumor growth, the host immune system must constantly clear harmful microorganisms and potentially malignant transformed cells. This task is accomplished in part by T-cells, which can directly kill infected or tumorigenic cells. A crucial event determining the recognition and elimination of detrimental cells is antigen recognition by the T cell receptor (TCR) expressed on the surface of T cells. Upon binding of the TCR to cognate peptide-MHC complexes presented on the surface of antigen presenting cells (APCs), a specialized supramolecular structure known as the immunological synapse (IS) assembles at the T cell-APC interface. Such a structure involves massive redistribution of membrane proteins, including TCR/pMHC complexes, modulatory receptor pairs, and adhesion molecules. Furthermore, assembly of the immunological synapse leads to intracellular events that modulate and define the magnitude and characteristics of the T cell response. Here, we discuss recent literature on the regulation and assembly of IS and the mechanisms evolved by tumors to modulate its function to escape T cell cytotoxicity, as well as novel strategies targeting the IS for therapy.
    Full-text · Article · Mar 2013 · Clinical and Developmental Immunology
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    • "Yet it is this promise that has drawn skepticism, but remains exciting for some because anti-Ids continue to prove their potential in the clinic (Bhattachary-Chatterjee et al., 2000; Bhattacharya- Chatterjee et al., 2001; Maruyama et al., 2000; Li et al., 2002; Ruffini et al., 2005; Lee et al., 2007; Neninger et al., 2007; Ai et al., 2009; Fernandez et al., 2010; Hernandez et al., 2011; Inoges et al., 2011; Ng et al., 2012). Perhaps the main weakness of the INT is its claim for generality while including a very restricted set of components and interactions in the immune system. "
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    ABSTRACT: A basic tenet of antibody-based immunity is their specificity to antigenic determinates from foreign pathogen products to abnormal cellular components such as in cancer. However, an antibody has the potential to bind to more than one determinate, be it an antigen or another antibody. These observations led to the idiotype network theory (INT) to explain immune regulation, which has wax and waned in enthusiasm over the years. A truer measure of the impact of the INT is in terms of the ideas that now form the mainstay of immunological research and whose roots are spawned from the promise of the anti-idiotype concept. Among the applications of the INT is understanding the structural implications of the antibody-mediated network that has the potential for innovation in terms of rational design of reagents with biological, chemical, and pharmaceutical applications that underlies concepts of reverse immunology which is highlighted herein.
    Full-text · Article · Dec 2012 · Frontiers in Oncology
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    • "Animals vaccinated with this diabody developed potent Id-specific antibody and T cell responses comparable to those induced by 38C13-KLH. Interestingly, such diabodies were produced in a cell-free protein expression system that allowed the preparation of proper amounts of vaccine in a few hours (Ng et al., 2012). "
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    ABSTRACT: Idiotype (Id)-based immunotherapy has been exploited as cancer treatment option. Conceived as therapy for malignancies bearing idiotypic antigens, it has been also extended to solid tumors because of the capacity of anti-idiotypic antibodies to mimic Id-unrelated antigens. In both these two settings, efforts are being made to overcome the poor immune responsiveness often experienced when using self immunoglobulins as immunogens. Despite bearing a unique gene combination, and thus particular epitopes, it is normally difficult to stimulate the immune response against antibody variable regions. Different strategies are currently used to strengthen Id immunogenicity, such as concomitant use of immune-stimulating molecules, design of Id-containing immunogenic recombinant proteins, specific targeting of relevant immune cells, and genetic immunization. This review focuses on the role of anti-Id vaccination in cancer management and on the current developments used to foster anti-idiotypic B and T cell responses.
    Full-text · Article · Nov 2012 · Frontiers in Oncology
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