A Chemically Induced Vaccine Strategy for Prostate Cancer

Three-component systems are often more complex than their two-component counterparts. Although the reversible association of three components in solution is critical for a vast array of chemical and biological processes, no general physical picture of such systems has emerged. Here we have developed a general, comprehensive framework for understanding ternary complex equilibria, which relates directly to familiar concepts such as “EC50” and “IC50” from simpler (binary complex) equilibria. Importantly, application of our model to data from the published literature has enabled us to achieve new insights into complex systems ranging from coagulation to therapeutic dosing regimens for monoclonal antibodies. We also provide an Excel spreadsheet to assist readers in both conceptualizing and applying our models. Overall, our analysis has the potential to render complex three-component systems – which have previously been characterized as “analytically intractable” – readily comprehensible to theoreticians and experimentalists alike.

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“…These and other predictions arising from our model have already proven useful in the ongoing pre-clinical development of these compounds. 46 …”

Section: Resultsmentioning

confidence: 99%

A Comprehensive Mathematical Model for Three-Body Binding Equilibria

Miller²,

et al. 2013

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“…Finally, cell-mediated cytotoxicity was dependent upon the presence of anti-DNP antibody; treatment of Hp with an isotype control antibody in place of anti-DNP led to only background levels of cell killing (Figure 5B). The specific cytotoxicity observed upon treatment with both azidosugar and phosphine (~25%) is on-par with what is required for cell killing in vivo [24] .…”

Section: Resultsmentioning

confidence: 99%

Recruiting the Host's Immune System to Target Helicobacter pylori's Surface Glycans

2013

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Due to the increased prevalence of bacterial strains that are resistant to existing antibiotics, there is an urgent need for new antibacterial strategies. Bacterial glycans are an attractive target for new treatments, as they are frequently linked to pathogenesis and contain distinctive structures that are absent in humans. We set out to develop a novel targeting strategy based on surface glycans present on the gastric pathogen Helicobacter pylori (Hp). In this study, metabolic labeling of bacterial glycans with an azide-containing sugar allowed selective delivery of immune stimulants to azide-covered Hp. We established that Hp’s surface glycans are labeled by treatment with the metabolic substrate peracetylated N-azidoacetylglucosamine (Ac4GlcNAz). By contrast, mammalian cells treated with Ac4GlcNAz exhibit no incorporation of the chemical label within extracellular glycans. We further demonstrated that the Staudinger ligation between azides and phosphines proceeds under acidic conditions with only a small loss of efficiency. We then targeted azide-covered Hp with phosphines conjugated to the immune stimulant 2,4-dinitrophenyl (DNP), a compound capable of directing a host immune response against these cells. Finally, we report that immune effector cells catalyze selective damage in vitro to DNP-covered Hp in the presence of anti-DNP antibodies. The technology reported herein represents a novel strategy to target Hp based on its glycans.

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“…(50,51,52,53,54) Despite these successes, relatively few examples of using small-molecules to redirect antibody-mediated immune responses against cancers have been disclosed. (28,29,30,31,32,33,34,35) Some of these approaches have shown promising results in animal studies using anti-hapten-immunized mice(29,30,35,55) or with injected antibody(31,32,33). The approach reported here differs from these prior strategies in that it targets uPAR, which is found on a broad variety of invasive cancer cells, and it also has the potential to exploit the naturally-occurring, hapten-directed class of anti-DNP antibodies for cancer cell destruction.…”

Section: Resultsmentioning

confidence: 99%

Reprogramming Urokinase into an Antibody-Recruiting Anticancer Agent

et al. 2011

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Synthetic compounds for controlling or creating human immunity have the potential to revolutionize disease treatment. Motivated by challenges in this arena, we report herein a strategy to target metastatic cancer cells for immune-mediated destruction by targeting the urokinase-type plasminogen activator receptor (uPAR). Urokinase-type plasminogen activator (uPA) and uPAR are overexpressed on the surfaces of a wide range of invasive cancer cells and are believed to contribute substantially to the migratory propensities of these cells. The key component of our approach is an antibody-recruiting molecule that targets the urokinase receptor (ARM-U). This bifunctional construct is formed by selectively, covalently attaching an antibody-binding small molecule to the active site of the urokinase enzyme. We demonstrate that ARM-U is capable of directing antibodies to the surfaces of target cancer cells and mediating both antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) against multiple human cancer cell lines. We believe that the reported strategy has the potential to inform novel treatment options for a variety of deadly, invasive cancers.

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A Chemically Induced Vaccine Strategy for Prostate Cancer

Cited by 44 publications

References 23 publications

A Comprehensive Mathematical Model for Three-Body Binding Equilibria

A Comprehensive Mathematical Model for Three-Body Binding Equilibria

Recruiting the Host's Immune System to Target Helicobacter pylori's Surface Glycans

Reprogramming Urokinase into an Antibody-Recruiting Anticancer Agent

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