Analysis of therapeutic and immunologic effects of R24 anti‐GD3 monoclonal antibody in 37 patients with metastatic melanoma

Kirkwood, John M.; Mascari, R.; Edington, Howard; Rabkin, Michael S.; Day, Roger; Whiteside, Theresa L.; Vlock, Daniel R.; Shipe-Spotloe, Janice

doi:10.1002/1097-0142(20000615)88:12<2693::aid-cncr7>3.3.co;2-v

Cited by 5 publications

(6 citation statements)

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“…Monoclonal antibodies against the gangliosides GD2 and GD3 for the therapy of malignant melanoma cells are effective in vitro and in mouse tumor models 24, 25, 26. However, the outcome of clinical studies in metastatic melanoma has been disappointing so far or showed only limited antitumor responses 27, 28. Also, a combination therapy of the chimeric anti‐GD2 antibody ch14.18 with IL‐2 did not lead to significant improved efficacy 29.…”

Section: Discussionmentioning

confidence: 99%

Two new trifunctional antibodies for the therapy of human malignant melanoma

Rosenberger

Jäger²,

Ellwart

et al. 2003

Intl Journal of Cancer

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Section: Discussionmentioning

confidence: 99%

Two new trifunctional antibodies for the therapy of human malignant melanoma

Rosenberger

Jäger²,

Ellwart

et al. 2003

Intl Journal of Cancer

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“…The anti‐idiotypic antibody approach represents an alternative to circumvent the poor immunogenicity of GD3 and the toxicity of the mAb R24 ( 11–14 ) in cancer therapy. The remarkable ability of anti‐Id antibodies to mimic the original antigen has been shown in several models.…”

Section: Discussionmentioning

confidence: 99%

“…( 9,10 ) Nevertheless, the dose‐dependent toxicity of R24 can be substantial and constitutes a serious limitation for its clinical use. ( 11–14 )…”

mentioning

confidence: 99%

The idiotype (Id) cascade in mice elicited the production of anti‐R24 Id and anti‐anti‐Id monoclonal antibodies with antitumor and protective activity against human melanoma

Ramos¹,

Parise²,

Travassos³

et al. 2010

Cancer Science

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Gangliosides have been considered as potential targets for immunotherapy because they are overexpressed on the surface of melanoma cells. However, immunization with purified gangliosides results in a very poor immune response, usually mediated by IgM antibodies. To overcome this limitation, we immunized mice with R24, a monoclonal antibody (mAb) that recognizes the most tumor-restricted ganglioside (GD3); our goal was to obtain antiidiotype (Id) antibodies bearing the internal image of GD3. Animals produced anti-Id and anti-anti-Id antibodies. Both anti-Id and anti-anti-Id antibodies were able to inhibit mAb R24 binding to GD3. In addition, the anti-anti-Id antibodies were shown to recognize GD3 directly. Anti-Id and anti-anti-Id mAb were then selected from two fusion experiments for evaluation. The most interesting finding emerged from the characterization of the antianti-Id mAb 5.G8. It was shown to recognize two different GD3-expressing human melanoma cell lines in vitro and to mediate tumor cell cytotoxicity by complement activation and antibodydependent cellular cytotoxicity. The biological activity of the antianti-Id mAb was also tested in a mouse tumor model, in which it was shown to be a powerful growth inhibitor of melanoma cells. Thus, activity of the anti-anti-Id mAb 5.G8 matched that of the prototypic anti-GD3 mAb R24 both in vitro and in vivo. Altogether, our results indicate that the idiotype approach might produce high affinity, specific and very efficient antitumor immune responses. (Cancer Sci 2011; 102: 64-70) M elanomas and other tumors of neuroectodermal origin have a distinct profile of cell-surface ganglioside expression.(1) The relevance of these carbohydrate antigens as immune targets in cancer cells can be inferred from earlier studies that described the ability of monoclonal antibodies (mAb) raised against gangliosides to induce complement-dependent cytotoxicity (CDC) in melanoma, neuroblastoma, sarcoma and astrocytoma cell lines.(2) Generally, immunization with whole tumor cells or cell lysates induces low titer IgM antibodies to carbohydrate antigens, but the use of conjugated vaccines can produce high titers of IgM and IgG antibodies.(3) The best vaccine design involves the conjugation of the antigen to keyhole limpet hemocyanin (KLH) and the use of saponins QS-21 and GPI-0100 as adjuvants. In contrast to normal cells, transformed melanocytes abundantly express disialoganglioside 3 (GD3). R24 is a mouse mAb that specifically recognizes GD3 and mediates in vitro effector functions such as CDC and antibody-dependent cellular cytotoxicity (ADCC).(5) It also stimulates proliferation of GD3-expressing T cells derived from human peripheral blood (6) and was shown to enhance lymphocyte RNA expression of IL-4, IL-10 and IFN-c.(7) Normal melanocytes are not lysed by the R24-directed immune response due to their low GD3 expression. In contrast to the potent in vitro activity of R24, its effect in nu ⁄ nu mice bearing human melanoma grafts is much more modest; tumor inhibition was observed o...

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“…Its antitumor effects may be related to increases in the expression of cytotoxic lymphocytes. 19,20 Other details of differences in chemotherapy regimens were not provided. Patients underwent quantitative FDG PET imaging at baseline, at days 3 and 10 of GM-CSF or M-CSF therapy, and 3 days following completion of treatment.…”

Section: Clinical Studiesmentioning

confidence: 99%