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Andreas Nechansky

Publications and source records attributed to Andreas Nechansky.

6 recordsLinked to original sources
PubMed2006

Compensation of endogenous IgG mediated inhibition of antibody-dependent cellular cytotoxicity by glyco-engineering of therapeutic antibodies.

A major limitation to the application of therapeutic IgG antibodies (Abs) is their reduced in vivo efficacy compared to their high efficacy as measured in vitro. Recently, Preithner et al. showed that the high amount of endogenous serum IgG impairs the antibody-dependent cellular cytotoxicity effector function (ADCC) of therapeutic Abs in vivo by competing for binding to Fcgamma-RIII on the effector cells. Modification of the glycosylation moieties attached to the Fc part of the Ab, e.g. de-fucosylation, has been shown to increase ADCC activity. We here show that the ADCC activity of a fucose-deficient, moss-produced therapeutic IgG is not impaired by normal human serum. The increased ADCC activity of the fucose-deficient Ab variant even in the presence of high endogenous IgG indicates that glyco-engineering of Abs may translate into improved clinical efficacy. Noteworthy, moss production of glyco-modified Abs should be applicable to a broad variety of therapeutic Abs currently in use indicative for the potential of this technology platform.

Antibodies, Monoclonal↗
PubMed2006

Immunization of Rhesus monkeys with a SialylTn-mAb17-1A conjugate vaccine co-formulated with QS-21 induces a temporary systemic cytokine release and NK cytotoxicity against tumor cells.

Tumor-associated antigens resulting from aberrant glycosylation, such as the SialylTn carbohydrate antigen, are frequently over-expressed on cancer cells and provide potential targets for cancer vaccination. Immunization of Rhesus monkeys with SialylTn coupled to a highly immunogenic carrier molecule and formulated on aluminum hydroxide induced a strong immune response against the carrier protein but only a moderate IgM immune response against the SialylTn carbohydrate antigen. Co-formulation with QS-21 adjuvant dramatically enhanced the anti-SialylTn immune response and resulted in a SialylTn-specific IgG switch. The kinetics of the carbohydrate-specific IgG response correlated with a temporary release of cytokines such as IFNgamma, IL-2, IL-1beta, TNFalpha and GM-CSF which was measurable in the immune serum by xMAP Multiplex technology. Furthermore, tumor cell killing by activated natural killer cells was induced. These data demonstrate that immunization with a tumor-associated carbohydrate antigen in a highly immunogenic formulation results in a temporary release of type 1 cytokines which may be required for the induction of a specific IgG immune response against the carbohydrate antigen as well as for activation of effector cells against tumor cells.

Adjuvants, Immunologic↗
PubMed2006

Cancer immunotherapy.

Cancer is the second leading cause of death in the industrialized world. Most cancer patients are treated by a combination of surgery, radiation and/or chemotherapy. Whereas the primary tumor can, in most cases, be efficiently treated by a combination of these standard therapies, preventing the metastatic spread of the disease through disseminated tumor cells is often not effective. The eradication of disseminated tumor cells present in the blood circulation and micro-metastases in distant organs therefore represents another promising approach in cancer immunotherapy. Main strategies of cancer immunotherapy aim at exploiting the therapeutic potential of tumor-specific antibodies and cellular immune effector mechanisms. Whereas passive antibody therapy relies on the repeated application of large quantities of tumor antigen-specific antibodies, active immunotherapy aims at the generation of a tumor-specific immune response combining both humoral and cytotoxic T cell effector mechanisms by the host's immune system following vaccination. In the first part of this review, concurrent developments in active and passive cancer immunotherapy are discussed. In the second part, the various approaches for the production of optimized monoclonal antibodies used for anti-cancer vaccination are summarized.

Animals↗
PubMed2005

Immunization of Rhesus monkeys with the conjugate vaccine IGN402 induces an IgG immune response against carbohydrate and protein antigens, and cancer cells.

Tumor-associated antigens resulting from aberrant glycosylation, such as the SialylTn carbohydrate antigen, are over-expressed on cancer cells and provide potential targets for cancer vaccination. However, as T-cell-independent antigens carbohydrates are poorly immunogenic, and fail to induce memory. In order to increase the immunogenicity we have coupled the SialylTn carbohydrate antigen to a highly immunogenic carrier molecule, the murine monoclonal antibody mAb17-1A. An immunogenic formulation of the SialylTn-mAb17-1A conjugate on alhydrogel, IGN402, with or without additional adjuvants was tested in Rhesus monkeys for tolerability and immunogenicity. A significant antibody response against mAb17-1A antibody was found. Importantly, also a specific immune response against SialylTn carbohydrate and binding to tumor cells was induced. Immunization in the presence of additional adjuvants, such as QS-21, strongly enhanced the immune response against the carbohydrate antigen, and resulted in induction of SialylTn-specific IgG antibodies. Noteworthy, also an induced temporary release of cytokines including IFNgamma and IL-2, indicative for T-cell activation, was measured. The data indicate that carrier-induced T-cell help together with strong adjuvant is sufficient for carbohydrate specific class switch induction.

Animals↗
PubMedDate not supplied

SialylTn-mAb17-1A carbohydrate-protein conjugate vaccine: effect of coupling density and presentation of SialylTn.

Carbohydrate antigens resulting from aberrant glycosylation of tumor cells, such as SialylTn, represent attractive targets for cancer vaccination. However, T-cell-independent carbohydrate antigens are poorly immunogenic and fail to induce memory and IgG class switch. Clustered expression patterns of some carbohydrates on the cell surface add further complexity to the design of carbohydrate-based vaccines. We describe here a vaccine consisting of SialylTn carbohydrate epitopes coupled to a highly immunogenic carrier molecule, mAb17-1A, adsorbed on alhydrogel and coformulated with a strong adjuvant, QS-21. The SialylTn-mAb17-1A conjugate vaccine was administered in Rhesus monkeys, and the immune responses against mAb17-1A, SialylTn, ovine submaxillary mucin, and tumor cells were analyzed. The data demonstrate that the density of carbohydrate epitopes on the carrier is an essential parameter for induction of anti-carbohydrate specific memory IgG immune responses. Furthermore, the influence of different types of presentation of SialylTn (monomeric vs trimers vs clustered via a branched polyethylenimine linker) on antibody titers and specificity was studied. High-density coupling of SialylTn epitopes to mAb17-1A induced the strongest immune response against synthetic SialylTn and showed also the highest reactivity against natural targets, such as OSM and tumor cells.

Animals↗