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A. N. Houghton - One of the best experts on this subject based on the ideXlab platform.
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The role of homophilic binding in anti-tumor antibody R24 recognition of molecular surfaces. Demonstration of an intermolecular beta-sheet interaction between vh domains.
The Journal of biological chemistry, 1999Co-Authors: M. J. Kaminski, P B Chapman, A. N. Houghton, C. R. Mackenzie, M. J. Mooibroek, T. E. S. Dahms, T. Hirama, S. V. EvansAbstract:The murine antibody R24 and mouse-human Fv-IgG1(kappa) chimeric antibody chR24 are specific for the cell-surface tumor antigen disialoganglioside GD3. X-ray diffraction and surface plasmon resonance experiments have been employed to study the mechanism of "homophilic binding," in which molecules of R24 recognize and bind to other molecules of R24 though their heavy chain variable domains. R24 exhibits strong binding to liposomes containing disialoganglioside GD3; however, the kinetics are unusual in that saturation of binding is not observed. The binding of chR24 to GD3-bearing liposomes is significantly weaker, suggesting that cooperative interactions involving antibody constant regions contribute to R24 binding of membrane-bound GD3. The crystal structures of the Fabs from R24 and chR24 reveal the mechanism for homophilic binding and confirm that the homophilic and antigen-binding idiotopes are distinct. The homophilic binding idiotope is formed largely by an anti-parallel beta-sheet dimerization between the H2 complementarity determining region (CDR) loops of two Fabs, while the antigen-binding idiotope is a pocket formed by the three CDR loops on the heavy chain. The formation of homophilic dimers requires the presence of a canonical conformation for the H2 CDR in conjunction with participation of side chains. The relative positions of the homophilic and antigen-binding sites allows for a lattice of GD3-specific antibodies to be constructed, which is stabilized by the presence of the cell membrane. This model provides for the selective recognition by R24 of cells that overexpress GD3 on the cell surface.
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Administration of R24 monoclonal antibody and low-dose interleukin 2 for malignant melanoma.
Clinical cancer research : an official journal of the American Association for Cancer Research, 1997Co-Authors: Robert J. Soiffer, Paul B. Chapman, A. N. Houghton, Heather Collins, Christopher J L Murray, Linda Williams, Pamela D. Unger, Jerome RitzAbstract:R24 is a monoclonal antibody that recognizes the disialoganglioside GD3 expressed on the surface of malignant melanoma cells. Once bound, it can mediate destruction of these cells through both complement-mediated lysis and antibody-dependent cellular cytotoxicity. Agents such as interleukin 2 (IL-2), which can augment effector cell function and promote destruction of antibody-coated tumor cells, might produce improved antitumor responses when combined with R24. In this series, we evaluated the combination of R24 and IL-2 in a Phase 1b study in patients with metastatic melanoma. Twenty-eight patients with metastatic melanoma were entered into the protocol at two institutions. Patients received 8 weeks of IL-2 by continuous i.v. infusion at a dose (4.5 x 10(5) Amgen units/m2/day) designed to selectively expand natural killer (NK) cells. In weeks 5 and 6, patients received R24 for a total of four doses. Twenty-four h after each R24 infusion, patients received a 2-h bolus dose of IL-2 to help promote activity of NK effectors against antibody-coated melanoma targets. Additional IL-2 boluses were administered in weeks 7 and 8. Doses were escalated through two bolus doses of R24 (5 or 15 mg/m2) and two bolus doses of IL-2 (2.5 or 5.0 x 10(5) units/m2). Although one patient experienced severe capillary leak syndrome during IL-2, therapy was otherwise well tolerated. At the higher dose level of R24, two of four patients experienced transient but severe abdominal and chest discomfort, necessitating dose reduction. One patient with ocular melanoma and liver metastases had a partial response. Two additional patients had minor responses. A dramatic increase in NK cell number was noted as a result of treatment, as was augmentation of cytolytic activity against cultured NK-sensitive targets. Antibody-dependent cellular cytotoxicity against cultured melanoma cells in the presence of exogenous R24 or in the presence of serum obtained from patients following R24 infusion also increased during treatment. Our experience indicates that R24 and low-dose IL-2 can be safely combined in patients with metastatic melanoma and that this combination can promote destruction of cultured melanoma cells. The clinical activity of this combination against ocular melanoma may merit further investigation.
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Increased proliferation, cytotoxicity, and gene expression after stimulation of human peripheral blood T lymphocytes through a surface ganglioside (GD3)
Journal of immunology (Baltimore Md. : 1950), 1994Co-Authors: Y. Norihisa, Daniel W. Mcvicar, Paritosh Ghosh, A. N. Houghton, Dan L. Longo, Stephen P. Creekmore, Trevor Blake, John R. Ortaldo, H A YoungAbstract:Previous studies have suggested that gangliosides have an important role in cell signaling and recognition. However, their specific function in these processes has not been clearly defined. A mAb, R24, that reacts specifically with a cell surface ganglioside (GD3) has been demonstrated to stimulate proliferation of T cells derived from human peripheral blood. In this study, we have investigated the mechanisms by which the R24 mAb affects T cell functions. We have observed that the R24 mAb stimulates GD3+ T cell proliferation, cytotoxicity, and surface marker expression of IL-2R alpha-chain, IL-2R beta-chain, HLA-DR, CD11a, and CD11c. Additionally, IFN-gamma activity but not IL-1, IL-2, or IL-4 activity was present in culture supernatants 72 h after R24 stimulation. In some donors, increased IL-6 and TNF-alpha activity also was detected after R24 treatment. Furthermore, R24 treatment resulted in translocation of c-rel, but little or no NF kappa B p50 or p65, from the cytoplasm to the nucleus and an increase of NF kappa B binding complexes containing c-rel and p50. This treatment also caused increased tyrosine phosphorylation of specific protein substrates. R24-stimulated increases in proliferation, cytotoxicity, and cell surface protein expression could be blocked by cyclosporin and staurosporin, indicating that cyclophilin/calcineurin and protein kinase C may be involved in the R24 signaling pathway. Additionally, herbimycin A, a tyrosine kinase inhibitor, blocked the R24-stimulated increase in proliferation but not cytotoxicity at concentrations consistent with specificity for tyrosine kinases. These results suggest that multiple biochemical pathways are involved in the activation of human T cells by R24.
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Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma
Blood, 1994Co-Authors: Lm Minasian, Paul B. Chapman, Linda Williams, Tp Szatrowski, Michael Rosenblum, Thomas A. Steffens, Me Morrison, Carl Nathan, A. N. HoughtonAbstract:Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.
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Treatment with high dose mouse monoclonal (anti-GD3) antibody R24 in patients with metastatic melanoma.
Melanoma research, 1992Co-Authors: Dean F. Bajorin, Herbert F. Oettgen, Carlos Cordon-cardo, P B Chapman, George Y. Wong, Lucy Dantes, B V Cody, M A Templeton, D Scheinberg, A. N. HoughtonAbstract:R24 is a mouse IgG3 monoclonal antibody that reacts with the ganglioside GD3 expressed by melanoma cells and other cells of neuroectodermal origin (e.g. adrenal medulla). Antitumour activity of R24 was demonstrated in initial phase I and pilot trials, but treatment was limited by urticaria at cumulative doses of 400 mg/m2. A trial exploring intensification of the dose of R24 was conducted in eight patients. Planned doses of R24 antibody were 800 and 1200 mg/m2 over 6-8 days by continuous i.v. infusion. All patients received concomitant therapy with hydroxyzine hydrochloride and cimetidine to minimize urticaria. One patient developed anaphylaxis, after which no further therapy was given. All patients developed peripheral blood lymphopenia and marked decreases in serum complement values during treatment, suggesting depletion of two possible effector mechanisms of the antitumour effects of R24. A vascular leak syndrome, manifested by weight gain, oedema and hypotension, was evident in seven patients during the initial 24-36 h of treatment. Serum sickness syndrome was observed in six of seven evaluable patients between days 5 and 8, coincident with the onset of the human anti-globulin response to R24. One patient given 1200 mg/m2 had a minor response (38% reduction in pelvic nodes) lasting 12 months. There was no detectable increase (by immunohistochemical staining) in deposition of R24 within tumour sites at doses used in this trial compared to that observed at doses of 240 and 400 mg/m2. The maximum tolerated dose was 800 mg/m2. Dose-limiting toxicity was manifest as reversible hypertension with end-organ symptoms (chest pain or visual field defects) in patients treated with a dose of 1200 mg/m2.(ABSTRACT TRUNCATED AT 250 WORDS)
Paul B. Chapman - One of the best experts on this subject based on the ideXlab platform.
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Anti-melanoma effects of R24, a monoclonal antibody against GD3 ganglioside.
Melanoma Research, 1997Co-Authors: M. Laura Nasi, Alan N. Houghton, Michael L. Meyers, Philip O. Livingston, Paul B. ChapmanAbstract:R24, a mouse monoclonal antibody against GD3 ganglioside, is potent at mediating in vitro effector functions such as human complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity, and can block melanoma tumor growth in animal models. Because of these properties and the fact that GD3 is abundantly expressed on virtually all melanomas but is found on few normal tissues, R24 has been tested in a series of clinical trials in patients with metastatic melanoma. As a single agent, R24 can induce responses in patients treated with metastatic melanoma. Overall, there have been 10 re-sponders out of 103 patients reported; two responses have been complete responses. Responses have largely occurred in patients treated with intermediate doses of R24 and have included complete responses. Combining R24 with either cytotoxic drugs or cytokines has not increased this response rate, although one trial with R24 and interleukin-2 resulted in a 43% response rate and merits further investigation. Local-regional treatments R24 (intratumor injections, regional limb perfusion, intrathecal administration) have also been attempted in a small number of patients and responses have been described. Taken together, multiple centers have reported responses in patients with metastatic melanoma treated with R24.
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Administration of R24 monoclonal antibody and low-dose interleukin 2 for malignant melanoma.
Clinical cancer research : an official journal of the American Association for Cancer Research, 1997Co-Authors: Robert J. Soiffer, Paul B. Chapman, A. N. Houghton, Heather Collins, Christopher J L Murray, Linda Williams, Pamela D. Unger, Jerome RitzAbstract:R24 is a monoclonal antibody that recognizes the disialoganglioside GD3 expressed on the surface of malignant melanoma cells. Once bound, it can mediate destruction of these cells through both complement-mediated lysis and antibody-dependent cellular cytotoxicity. Agents such as interleukin 2 (IL-2), which can augment effector cell function and promote destruction of antibody-coated tumor cells, might produce improved antitumor responses when combined with R24. In this series, we evaluated the combination of R24 and IL-2 in a Phase 1b study in patients with metastatic melanoma. Twenty-eight patients with metastatic melanoma were entered into the protocol at two institutions. Patients received 8 weeks of IL-2 by continuous i.v. infusion at a dose (4.5 x 10(5) Amgen units/m2/day) designed to selectively expand natural killer (NK) cells. In weeks 5 and 6, patients received R24 for a total of four doses. Twenty-four h after each R24 infusion, patients received a 2-h bolus dose of IL-2 to help promote activity of NK effectors against antibody-coated melanoma targets. Additional IL-2 boluses were administered in weeks 7 and 8. Doses were escalated through two bolus doses of R24 (5 or 15 mg/m2) and two bolus doses of IL-2 (2.5 or 5.0 x 10(5) units/m2). Although one patient experienced severe capillary leak syndrome during IL-2, therapy was otherwise well tolerated. At the higher dose level of R24, two of four patients experienced transient but severe abdominal and chest discomfort, necessitating dose reduction. One patient with ocular melanoma and liver metastases had a partial response. Two additional patients had minor responses. A dramatic increase in NK cell number was noted as a result of treatment, as was augmentation of cytolytic activity against cultured NK-sensitive targets. Antibody-dependent cellular cytotoxicity against cultured melanoma cells in the presence of exogenous R24 or in the presence of serum obtained from patients following R24 infusion also increased during treatment. Our experience indicates that R24 and low-dose IL-2 can be safely combined in patients with metastatic melanoma and that this combination can promote destruction of cultured melanoma cells. The clinical activity of this combination against ocular melanoma may merit further investigation.
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Mapping effector functions of a monoclonal antibody to GD3 by characterization of a mouse-human chimeric antibody.
Cancer immunology immunotherapy : CII, 1994Co-Authors: Paul B. Chapman, Alan N. Houghton, Stephen D. Gillies, Regina M. ReillyAbstract:R24, a mouse monoclonal antibody against GD3 ganglioside, exhibits a wide range of in vitro effector functions. It also has the ability to bind to itself, presumably through homophilic Fab-Fab interactions, which have been proposed to contribute to its high relative avidity for GD3 and to its effector function activity. It is not known which of these characteristics is necessary for the antitumor effects observed in melanoma patients treated with R24. A mouse-human chimeric R24 (chR24) molecule has been constructed in which the GD3-binding site is preserved. Chimeric R24 demonstrates a lower level of binding to GD3 than does mouse R24 suggesting that there may be some differences between the GD3-binding sites of the two mAb or that Fc determinants can contribute to R24 avidity for GD3. The property of homophilic binding is retained by chR24, demonstrating formally that homophilic binding of R24 involves interactions between variable domains. Both R24 and chR24 fix human complement and mediate antibody-dependent cellular cytotoxicity although chR24 was slightly less efficient at the latter. Unlike R24, chR24 was not able to inhibit melanoma cell attachment to plastic surfaces and was not able to activate human T lymphocytes. We hypothesize that chR24 does not bind to GD3 with an avidity high enough to mediate these effector functions.
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Hemorrhagic tumor necrosis during a pilot trial of tumor necrosis factor-alpha and anti-GD3 ganglioside monoclonal antibody in patients with metastatic melanoma
Blood, 1994Co-Authors: Lm Minasian, Paul B. Chapman, Linda Williams, Tp Szatrowski, Michael Rosenblum, Thomas A. Steffens, Me Morrison, Carl Nathan, A. N. HoughtonAbstract:Hemorrhagic tumor necrosis is an inflammatory event that leads to selective destruction of malignant tissues, with both potentially toxic and beneficial consequences. A pilot clinical trial was undertaken combining tumor necrosis factor-alpha (TNF-alpha) with the monoclonal antibody R24 (MoAb R24) against GD3 ganglioside in patients with metastatic melanoma. Patients received MoAb R24 to recruit leukocytes to the tumor followed by low doses of recombinant TNF-alpha to activate leukocytes. Eight patients were treated and seven patients had mild toxicity. One patient with extensive metastatic melanoma developed tumor lysis syndrome within hours after treatment with almost complete necrosis of bulky tumors in multiple visceral sites. To our knowledge, this is the first documented case of hemorrhagic tumor necrosis in a patient with metastatic cancer in multiple visceral sites.
Alan N. Houghton - One of the best experts on this subject based on the ideXlab platform.
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Anti-melanoma effects of R24, a monoclonal antibody against GD3 ganglioside.
Melanoma Research, 1997Co-Authors: M. Laura Nasi, Alan N. Houghton, Michael L. Meyers, Philip O. Livingston, Paul B. ChapmanAbstract:R24, a mouse monoclonal antibody against GD3 ganglioside, is potent at mediating in vitro effector functions such as human complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity, and can block melanoma tumor growth in animal models. Because of these properties and the fact that GD3 is abundantly expressed on virtually all melanomas but is found on few normal tissues, R24 has been tested in a series of clinical trials in patients with metastatic melanoma. As a single agent, R24 can induce responses in patients treated with metastatic melanoma. Overall, there have been 10 re-sponders out of 103 patients reported; two responses have been complete responses. Responses have largely occurred in patients treated with intermediate doses of R24 and have included complete responses. Combining R24 with either cytotoxic drugs or cytokines has not increased this response rate, although one trial with R24 and interleukin-2 resulted in a 43% response rate and merits further investigation. Local-regional treatments R24 (intratumor injections, regional limb perfusion, intrathecal administration) have also been attempted in a small number of patients and responses have been described. Taken together, multiple centers have reported responses in patients with metastatic melanoma treated with R24.
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R24 anti-GD3 ganglioside antibody can induce co-stimulation and prevent the induction of alloantigen-specific T cell clonal anergy
European Journal of Immunology, 1996Co-Authors: Vassiliki A. Boussiotis, Alan N. Houghton, Nichole A. Pardo, Heather Collins, Jerome Ritz, Lee M. Nadler, Robert J. SoifferAbstract:: R24 is a monoclonal antibody directed against the cell surface ganglioside GD3. It can detect GD3 on the surface of a subset of T lymphocytes and can stimulate proliferation and secretion of cytokines in vitro. In the present report, we examined the effects of the R24 antibody upon antigen-specific T cell response, employing an HLA-DR7-specific T cell clonal model. As previously shown, primary stimulation of HLA-DR7-specific alloreactive T cell clones by transfectants expressing HLA-DR7 alone (t-DR7) in the absence of B7 co-stimulation resulted in anergy. Binding of cell surface GD3 on HLA-DR7-specific alloreactive T cell clones with R24 under these anergizing conditions resulted in interleukin-2 (IL-2) accumulation and prevented the induction of alloantigen-specific T cell clonal anergy. Binding of GD3 by R24 also prevented anergy under conditions where B7:CD28 interactions were blocked by CTLA4-Ig. The effect of R24 was abrogated in the presence of a combination of monoclonal antibodies for the alpha and beta chains of the IL-2 receptor (IL-2R) or a neutralizing anti-IL-2 antibody. R24 does not appear to interact directly with the IL-2R since incubation of T cell clones with R24 did not induce early activation of IL-2R associated Jak kinases, Jak1 and Jak3, as was induced following incubation with IL-2. In contrast, incubation of HLA-DR7-specific clones with t-DR7 in the presence of R24 did result in phosphorylation of IL-2R related Jak kinases after 24 h. Our data indicate that the membrane ganglioside GD3 structure recognized by R24 may play an important role in antigen-specific T cell clonal response.
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Mapping effector functions of a monoclonal antibody to GD3 by characterization of a mouse-human chimeric antibody.
Cancer immunology immunotherapy : CII, 1994Co-Authors: Paul B. Chapman, Alan N. Houghton, Stephen D. Gillies, Regina M. ReillyAbstract:R24, a mouse monoclonal antibody against GD3 ganglioside, exhibits a wide range of in vitro effector functions. It also has the ability to bind to itself, presumably through homophilic Fab-Fab interactions, which have been proposed to contribute to its high relative avidity for GD3 and to its effector function activity. It is not known which of these characteristics is necessary for the antitumor effects observed in melanoma patients treated with R24. A mouse-human chimeric R24 (chR24) molecule has been constructed in which the GD3-binding site is preserved. Chimeric R24 demonstrates a lower level of binding to GD3 than does mouse R24 suggesting that there may be some differences between the GD3-binding sites of the two mAb or that Fc determinants can contribute to R24 avidity for GD3. The property of homophilic binding is retained by chR24, demonstrating formally that homophilic binding of R24 involves interactions between variable domains. Both R24 and chR24 fix human complement and mediate antibody-dependent cellular cytotoxicity although chR24 was slightly less efficient at the latter. Unlike R24, chR24 was not able to inhibit melanoma cell attachment to plastic surfaces and was not able to activate human T lymphocytes. We hypothesize that chR24 does not bind to GD3 with an avidity high enough to mediate these effector functions.
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Expression of disialogangliosides GD2 and GD3 on human soft tissue sarcomas
Cancer, 1992Co-Authors: Helena R. Chang, Alan N. Houghton, Carlos Cordon-cardo, Nai-kong V. Cheung, Murray F. BrennanAbstract:Methods. Fifty-six freshly frozen human sarcomas were studied for expression of disialogangliosides by avi-din-biotin immunohistochemical staining with purified monoclonal antibodies (MoAb) 3F8 (antidisialoganglioside GD2) and R24 (antidisialoganglioside GD3). Results. Ninety-three percent of the tumors tested by the immunohistochemical staining expressed GD2 and 88% expressed GD3. The intensity of expression varied among sarcomas of different histologic types. Lipo-sarcoma, fibrosarcoma, malignant fibrous histiocytoma, leiomyosarcoma, and spindle cell sarcoma reacted strongly with 3F8 and R24. Embryonal rhabdomyosarcoma and synovial sarcoma demonstrated substantially weaker staining by either MoAb. Weakly reactive or nonreactive tumors were, in general, high-grade or meta-static sarcomas. Ganglioside extraction and thin-layer chromatography/immunothin-layer chromatography of two liposarcomas confirmed the identities of these gangliosides. Conclusions. GD2 and GD3 may indicate sites for MoAb-targeted imaging and therapy for sarcomas. The association of a diminished stainability by 3F8 and R24 with aggressive sarcomas may indicate prognostic significance. Cancer 1992; 70:633–638.
Jose L. Daniotti - One of the best experts on this subject based on the ideXlab platform.
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Targeted Delivery of Immunotoxin by Antibody to Ganglioside GD3: A Novel Drug Delivery Route for Tumor Cells
PloS one, 2013Co-Authors: Vanina Torres Demichelis, Aldo Alejandro Vilcaes, Ramiro Iglesias-bartolome, Fernando M. Ruggiero, Jose L. DaniottiAbstract:Gangliosides are sialic acid-containing glycolipids expressed on plasma membranes from nearly all vertebrate cells. The expression of ganglioside GD3, which plays essential roles in normal brain development, decreases in adults but is up regulated in neuroectodermal and epithelial derived cancers. R24 antibody, directed against ganglioside GD3, is a validated tumor target which is specifically endocytosed and accumulated in endosomes. Here, we exploit the internalization feature of the R24 antibody for the selective delivery of saporin, a ribosome-inactivating protein, to GD3-expressing cells [human (SK-Mel-28) and mouse (B16) melanoma cells and Chinese hamster ovary (CHO)-K1 cells]. This immunotoxin showed a specific cytotoxicity on tumor cells grew on 2D monolayers, which was further evident by the lack of any effect on GD3-negative cells. To estimate the potential antitumor activity of R24-saporin complex, we also evaluated the effect of the immunotoxin on the clonogenic growth of SK-Mel-28 and CHO-K1GD3+ cells cultured in attachment-free conditions. A drastic growth inhibition (>80–90%) of the cell colonies was reached after 3 days of immunotoxin treatment. By the contrary, colonies continue to growth at the same concentration of the immuntoxin, but in the absence of R24 antibody, or in the absence of both immunotoxin and R24, undoubtedly indicating the specificity of the effect observed. Thus, the ganglioside GD3 emerge as a novel and attractive class of cell surface molecule for targeted delivery of cytotoxic agents and, therefore, provides a rationale for future therapeutic intervention in cancer.
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the antibody to gd3 ganglioside R24 is rapidly endocytosed and recycled to the plasma membrane via the endocytic recycling compartment inhibitory effect of brefeldin a and monensin
FEBS Journal, 2006Co-Authors: Ramiro Iglesiasbartolome, Pilar M Crespo, Guillermo A Gomez, Jose L. DaniottiAbstract:Gangliosides are sialic acid-containing glycosphingolipids present on mammalian plasma membranes, where they participate in cell-surface events such as modulation of growth factor receptors and cell-to-cell and cell-tomatrix interactions. Antibodies to gangliosides have been associated with a wide range of clinically identifiable acute and chronic neuropathy syndromes. In addition, antibodies to tumor-associated gangliosides are being used as therapeutic agents. Their binding to and release from cell membranes and intracellular destinations have not so far been extensively examined. In this study, we characterized in both GD3 ganglioside-expressing Chinese hamster ovary (CHO)-K1 and SK-Mel 28 melanoma cells the intracellular trafficking and subcellular localization of the mouse monoclonal antibody to GD3, R24. By biochemical techniques and detailed confocal microscopic analysis, we demonstrate that the GD3–R24 antibody complex is rapidly and specifically internalized by a dynamin 2-independent pathway and then accumulates in the endocytic recycling compartment. In addition, we show that the R24 antibody exits the recycling compartment en route to the plasma membrane by a dynamin 2-dependent pathway sensitive to brefeldin A and monensin. Taken together, our results indicate that the GD3–R24 complex is endocytosed in GD3-expressing cells, accumulates in the recycling endosome, and is transported back to the plasma membrane via a route that involves clathrin-coated vesicles.
Mark R. Albertini - One of the best experts on this subject based on the ideXlab platform.
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Phase I trial of combined treatment with ch14.18 and R24 monoclonal antibodies and interleukin-2 for patients with melanoma or sarcoma
Cancer Immunology Immunotherapy, 2006Co-Authors: Brian S. Choi, Paul M. Sondel, Jacquelyn A. Hank, Heidi Schalch, David M. King, Kari Kendra, David Mahvi, Mark R. AlbertiniAbstract:Purpose : We conducted a phase I trial of interleukin 2 (IL-2) in combination with chimeric 14.18 (ch14.18) and murine R24 antibodies to determine the maximal tolerated dose (MTD), immunological effects, and toxicity of this treatment combination. Experimental Design : Twenty-seven patients with either melanoma (23 patients) or sarcoma (4 patients) were enrolled to receive a combination therapy with ch14.18 and R24 antibodies together with continuous infusion of Roche IL-2 (1.5×10^6 U/m^2/day, 26 patients) or Chiron IL-2 (4.5×10^6 U/m^2/day, 1 patient) given 4 days/week for 3 weeks. The antibodies ch14.18 (2–7.5 mg/m^2/day) and R24 (1–10 mg/m^2/day) were scheduled to be administered for 5 days during the second week of IL-2 therapy. Results : When given in combination in this study, the MTD for ch14.18 was 5 mg/m^2/day and the MTD for R24 was 5 mg/m^2/day. Dose-limiting toxicities were severe allergic reactions to both ch14.18 and R24 as well as pain related to ch14.18. This ch14.18 MTD was lower than the 7.5 mg/m^2/day MTD previously determined for ch14.18 given alone with the same dose and schedule of IL-2. Immunological effects included the induction of lymphokine-activated killer (LAK) activity and antibody-dependent cell-mediated cytoxicity (ADCC). Anti-idiotype response to ch14.18 was seen in six patients, including two melanoma patients who had a partial response to treatment. In addition to two partial responses, four patients had a stable disease and one patient remained without any evidence of disease. Conclusions : Immunotherapy with IL-2 in combination with ch14.18 and R24 antibodies augments LAK function and ADCC measured in vitro in all patients. While there exist theoretical advantages of combining these two antibodies, the MTD of ch14.18 and of R24 were lower than the MTD of each antibody in prior studies evaluating single antibody therapy with IL-2. As such, the combination of these two antibodies together with IL-2 therapy appeared to influence the MTD and toxicity of each of the administered antibodies.
