A Fully Synthetic Globo H Carbohydrate Vaccine Induces a Focused Humoral Response in Prostate Cancer Patients: A Proof of Principle

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131

The carbohydrate antigen globo H commonly found on breast cancer cells is a potential target for vaccine therapy. The objectives of this trial were to determine the toxicity and immunogenicity of three synthetic globo H-keyhole limpet hemocyanin conjugates plus the immunologic adjuvant QS-21. Twenty-seven metastatic breast cancer patients received five vaccinations each. The vaccine was well tolerated, and no definite differences were observed among the three formulations. Serologic analyses demonstrated the generation of IgM antibody titers in most patients, with minimal IgG antibody stimulation. There was significant binding of IgM antibodies to MCF-7 tumor cells in 16 patients, whereas IgG antibody reactivity was observed in a few patients. There was evidence of complement-dependent cytotoxicity in several patients. Affinity column purification supported the specificity of IgM antibodies for globo H. On the basis of these data, globo H will constitute one component of a polyvalent vaccine for evaluation in high-risk breast cancer patients.

Section: Methodsmentioning

confidence: 99%

Section: Immunization Of Metastatic Breast Cancer Patients With a Fulmentioning

confidence: 99%

Immunization of metastatic breast cancer patients with a fully synthetic globo H conjugate: A phase I trial

Gilewski

Ragupathi

Bhuta

et al. 2001

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196

131

“…A multivalent glycan vaccine or carbohydrate conjugated with a carrier protein and administered with an immunological adjuvant has been adopted to increase the immunogenicity of carbohydrates. As an example, a GH vaccine with ∼700 GH units conjugated to one keyhole limpet hemocyanin (KLH) protein was prepared and administered together with a mixture of saponins called QS21 adjuvant (18,(22)(23)(24)(25), and it had been shown that treatment of mice with GH-KLH/QS21 could induce antisera against GH-positive cell lines without autoimmune reactions (14,23). Furthermore, the vaccine was fairly well-tolerated in a phase I clinical trial for metastatic breast cancer patients.…”

mentioning

confidence: 99%

Carbohydrate-based vaccines with a glycolipid adjuvant for breast cancer

Huang

Hung

Cheung

et al. 2013

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Globo H (GH) is a hexasaccharide specifically overexpressed on a variety of cancer cells and therefore, a good candidate for cancer vaccine development. To identify the optimal carrier and adjuvant combination, we chemically synthesized and linked GH to a carrier protein, including keyhole limpet hemocyanion, diphtheria toxoid cross-reactive material (CRM) 197 (DT), tetanus toxoid, and BSA, and combined with an adjuvant, and it was administered to mice for the study of immune response. Glycan microarray analysis of the antiserum obtained indicated that the combination of GH-DT adjuvanted with the α-galactosylceramide C34 has the highest enhancement of anti-GH IgG. Compared with the phase III clinical trial vaccine, GHkeyhole limpet hemocyanion/QS21, the GH-DT/C34 vaccine elicited more IgG antibodies, which are more selective for GH and the GHrelated epitopes, stage-specific embryonic antigen 3 (SSEA3) and SSEA4, all of which were specifically overexpressed on breast cancer cells and breast cancer stem cells with SSEA4 at the highest level (>90%). We, therefore, further developed SSEA4-DT/C34 as a vaccine candidate, and after immunization, it was found that the elicited antibodies are also IgG-dominant and very specific for SSEA4.carbohydrate vaccine | diphtheria toxin

“…Furthermore, it has been established that the serum of breast cancer patients contains high levels of antibodies against the Globo H epitope, and this epitope is also targeted by the monoclonal antibodies MBr1 (5-7) and VK-9 (8). As a result, this hexasaccharide has been the focus of studies aimed at anticancer vaccine development (9)(10)(11)(12)(13)(14)(15). Many elegant syntheses of Globo H have been reported (11,(16)(17)(18)(19)(20)(21)(22)(23)(24), including one approach that uses the one-pot programmable oligosaccharide synthesis developed in our laboratory (25).…”

mentioning

confidence: 99%

Carbohydrate microarray for profiling the antibodies interacting with Globo H tumor antigen

Huang

Thayer

Chang

et al. 2005

187

149

Understanding the specificity of cell-surface carbohydrates interaction with antibodies and receptors is important for the development of new therapeutics and high-sensitivity diagnostics. This approach is, however, limited to the availability of natural and truncated sequences of the oligosaccharides and the sensitivity of the assay system. Reported here is the synthesis of the cancer antigen Globo H hexasaccharide, an epitope found on the cell surface of breast, prostate, and ovarian cancers, and its truncated sequences by using the programmable one-pot synthesis strategy. The saccharides were then arrayed covalently on glass slides with different density and used for the fluorencense-based binding analysis of two monoclonal antibodies against Globo H and the serum from breast cancer patients, to define the specificity of these antibodies. It was shown that the terminal tetrasaccharide binds the monoclonal antibodies equally well as does the hexasaccharide and the fucose residue is required for effective binding. The serum binds both the defucosylated pentasaccharide and the fucosylated hexasaccharide without a significant difference, perhaps because of the polyclonal nature of the serum or the presence of diverse immune responses to different sugar epitopes at various stages. This method requires very small amounts of materials and is more effective and sensitive than the traditional ELISA method, and thus provides another platform to monitor the immune response to carbohydrate epitopes at different stages during differentiation, metastasis, or treatment.programmable one-pot synthesis ͉ glycoarray ͉ glycan epitope ͉ Globo H-truncated sequences T he cell-surface glycosphingolipid Globo H is a member of a family of antigenic carbohydrates that are highly expressed on a range of cancer cell lines, especially breast cancer cells (1-4). Furthermore, it has been established that the serum of breast cancer patients contains high levels of antibodies against the Globo H epitope, and this epitope is also targeted by the monoclonal antibodies MBr1 (5-7) and VK-9 (8). As a result, this hexasaccharide has been the focus of studies aimed at anticancer vaccine development (9-15). Many elegant syntheses of Globo H have been reported (11,(16)(17)(18)(19)(20)(21)(22)(23)(24), including one approach that uses the one-pot programmable oligosaccharide synthesis developed in our laboratory (25). Previously, it has been reported that certain truncated Globo H derivatives can still be effective in binding MBr1 and VK-9 antibodies, which could increase the efficiency of immunogen development for vaccine therapy (8,(26)(27)(28)(29)(30). We set out to further characterize the binding specificities of these and cancer patient antibodies by using carbohydrate microarray analysis.Carbohydrate microarrays allow for the direct characterization of carbohydrate-protein interactions. In addition, the attachment of sugars to surfaces can effectively mimic the presentation of these compounds on the cell membrane. A large factor which is present...