Abstract:Immunotherapy is a promising strategy for targeting tumors. One emerging approach is to harness the immune effector functions of natural antibodies to destroy tumor cells. Dinitrophenyl (DNP) and the galactose-α-1,3-galactose (αGal) epitope are two haptens that bind endogenous antibodies. One potential alternative is the deoxysugar L-rhamnose. We compared these candidates using a biosensor assay to evaluate human sera for endogenous antibody concentration, antibody isotype distribution, and longevity of antibo… Show more
“…9, 50, 51 In fact, Rha is now one of the most effective natural antibody eliciting molecules known 52 and Rha has been conjugated to lipids to recruit anti-Rha antibodies to tumor cells. 53, 54 …”
Generation of a CD8+ response to extracellular antigen requires processing of the antigen by antigen presenting cells (APC) and cross-presentation to CD8+ T cell receptors via MHC class I molecules. Cross-presentation is facilitated by efficient antigen uptake followed by immune-complex-mediated maturation of the APCs. We hypothesize that improved antigen uptake of a glycopeptide sequence containing a CD8+ T cell epitope could be achieved by delivering it on a liposome surface decorated with an immune complex-targeting ligand, an L-Rhamnose (Rha) epitope. We synthesized a 20 amino acid glycopeptide TSAPDT(GalNAc)RPAPGSTAPPAHGV from the variable number tandem repeat region of the tumor marker MUC1 containing an N-terminal azido moiety and a tumor-associated α-N-acetyl galactosamine (GalNAc) at the immunogenic DTR motif. The MUC1 antigen was attached to Pam3Cys, a Toll-like receptor-2 ligand via copper (I)-catalyzed azido-alkyne cycloaddtion (CuAAc) chemistry. The Rha-decorated liposomal Pam3Cys-MUC1-Tn 4 vaccine was evaluated in groups of C57BL/6 mice. Some groups were previously immunized to generate anti-Rha antibodies. Anti-Rha antibody expressing mice that received the Rha liposomal vaccine showed higher cellular immunogenicity compared to the control group while maintaining a strong humoral response.
“…9, 50, 51 In fact, Rha is now one of the most effective natural antibody eliciting molecules known 52 and Rha has been conjugated to lipids to recruit anti-Rha antibodies to tumor cells. 53, 54 …”
Generation of a CD8+ response to extracellular antigen requires processing of the antigen by antigen presenting cells (APC) and cross-presentation to CD8+ T cell receptors via MHC class I molecules. Cross-presentation is facilitated by efficient antigen uptake followed by immune-complex-mediated maturation of the APCs. We hypothesize that improved antigen uptake of a glycopeptide sequence containing a CD8+ T cell epitope could be achieved by delivering it on a liposome surface decorated with an immune complex-targeting ligand, an L-Rhamnose (Rha) epitope. We synthesized a 20 amino acid glycopeptide TSAPDT(GalNAc)RPAPGSTAPPAHGV from the variable number tandem repeat region of the tumor marker MUC1 containing an N-terminal azido moiety and a tumor-associated α-N-acetyl galactosamine (GalNAc) at the immunogenic DTR motif. The MUC1 antigen was attached to Pam3Cys, a Toll-like receptor-2 ligand via copper (I)-catalyzed azido-alkyne cycloaddtion (CuAAc) chemistry. The Rha-decorated liposomal Pam3Cys-MUC1-Tn 4 vaccine was evaluated in groups of C57BL/6 mice. Some groups were previously immunized to generate anti-Rha antibodies. Anti-Rha antibody expressing mice that received the Rha liposomal vaccine showed higher cellular immunogenicity compared to the control group while maintaining a strong humoral response.
“…115 ARMs bind target cells on one end and display a recruiting antigen on the other end that binds known native or supplemented antibodies. 117,118 The history and varied use of ARMs has been recently reviewed. 116) and prostate cancer 117 most recently.…”
Organisms depend upon complex intercellular communication to initiate, maintain, or suppress immune responses during infection or disease. Communication occurs not only between different types of immune cells, but also between immune cells and nonimmune cells or pathogenic entities. It can occur directly at the cell-cell contact interface, or indirectly through secreted signals that bind cell surface molecules. Though secreted signals can be soluble, they can also be particulate in nature and direct communication at the cell-particle interface. Secreted extracellular vesicles are an example of native particulate communication, while viruses are examples of foreign particulates. Inspired by communication at natural immunological interfaces, biomimetic materials and designer molecules have been developed to mimic and direct the type of immune response. This review describes the ways in which native, biomimetic, and designer materials can mediate immune responses. Examples include extracellular vesicles, particles that mimic immune cells or pathogens, and hybrid designer molecules with multiple signaling functions, engineered to target and bind immune cell surface molecules. Interactions between these materials and immune cells are leading to increased understanding of natural immune communication and function, as well as development of immune therapeutics for the treatment of infection, cancer, and autoimmune disease.
“…During infections, bacterial cells manage to escape the actions of the immune system. We hypothesized that a novel method to combat bacterial infections may be achieved through realerting the immune system to the presence of bacteria by tagging their surfaces with antigenic small molecules …”
During the past few decades there has been a rapid emergence of multidrug resistant bacteria afflicting human patients. At the same time, reduced output from pharmaceutical industry in this area precipitated a sharp decrease in the approval of new antibiotics. The combination of these factors potentially compromises the ability to effectively combat bacterial infections. While traditional drug discovery efforts continue in the pursuit of small molecule agents that disrupt bacterial growth, non-traditional efforts could serve to complement antimicrobial strategies. We recently demonstrated our ability to remodel the surface of bacterial cells using unnatural D-amino acids displaying the antigenic dinitrophenyl (DNP) handle. These immune stimulant D-amino acids derivatives were metabolically incorporated onto the peptidoglycan of bacteria via a promiscuous surface-anchored transpeptidase. The covalent modification of DNP moieties onto the peptidoglycan led to the anti-DNP antibody opsonization of the bacterial cell surface. Herein, we show that the amidation of the C-terminus to generate DNP-displaying D-amino carboxamide drastically improves antibody recruitment. Antibody opsonization using the D-amino carboxamide agent is observed at lower concentrations than the D-amino acid counterpart. In addition, the recruitment of endogenous antibodies in pooled human serum to the DNP-modified bacterial cell surface is demonstrated for the first time. We envision that the C-terminus amidation of DNP-conjugated D-amino acids could potentially facilitate translation of these results to in vivo animal disease models.
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