Article

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: 9.68). 08/2012; 109(36):14526-31. DOI:10.1073/pnas.1211018109 pp.14526-31
Source: PubMed

ABSTRACT 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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  • Article: Targeting of antigens to B cells augments antigen-specific T-cell responses and breaks immune tolerance to tumor-associated antigen MUC1.
    Chuanlin Ding, Li Wang, Jose Marroquin, Jun Yan
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    ABSTRACT: B cells are antibody (Ab)-secreting cells as well as potent antigen (Ag)-presenting cells that prime T-cell activation, which evokes great interest in their use for vaccine development. Here, we targeted ovalbumin (OVA) to B cells via CD19 and found that a single low dose of anti-CD19-OVA conjugates, but not isotype mAb-OVA, stimulated augmented CD4 and CD8 T-cell proliferation and expansion. Administration of TLR9 agonist CpG could significantly enhance long-term T-cell survival. Similar results were obtained when the tumor-associated Ag MUC1 was delivered to B cells. MUC1 transgenic (Tg) mice were previously found to lack effective T-cell help and produce low-titer of anti-MUC1 Abs after vaccination. Targeting MUC1 to B cells elicited high titer of anti-MUC1 Abs with different isotypes, predominantly IgG2a and IgG2b, in MUC1 Tg mice. The isotype switching of anti-MUC1 Ab was CD4 dependent. In addition, IFN-gamma-producing CD8 T cells and in vivo cytolytic activity were significantly increased in these mice. The mice also showed significant resistance to MUC1(+) lymphoma cell challenge both in the prophylactic and therapeutic settings. We conclude that Ags targeting to B cells stimulate CD4 and CD8 T-cell responses as well as Th-dependent humoral immune responses.
    Blood 08/2008; 112(7):2817-25. · 9.90 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

antigen presentation array
 
B-cell tumor
 
B-cell-targeting moiety
 
bind
 
cell-free protein expression system
 
Clinical studies
 
diabody linker augmented
 
favorable clinical outcomes
 
Id vaccine
 
induced anti-Id antibody responses
 
lymphoma Id
 
noncognate B cells
 
Peptide epitopes present
 
rare Id-specific B cells
 
robust Id-specific antibody response
 
small diabody
 
specific Ig genes
 
vaccinate patients
 
αCD19-Id molecule
 
αCD19-Id molecule induced