Phase I trial of a mouse monoclonal antibody against GD3 ganglioside in patients with melanoma: induction of inflammatory responses at tumor sites.

Abstract

Twenty-one patients were entered into a phase I trial to evaluate toxicity, antitumor effects, and biological responses at tumor sites during treatment of R24, an immunoglobulin G3 (IgG3) mouse monoclonal antibody (mAb) against GD3 ganglioside. Toxicity was related to dose of R24. Urticaria and pruritus were the most prominent side effects, with nausea, vomiting, and diarrhea occurring at the highest dose levels. Partial responses were observed in four patients lasting from 6 to 46 weeks, and mixed responses were seen in two patients. Responses occurred as early as 4 weeks and as late as 10 weeks after beginning treatment. Twenty of the 21 patients developed human IgG antibodies against R24. Antimouse Ig antibodies were first detected at a median of 14 days after starting treatment, but three of the four patients who had a partial response developed the antimouse Ig responses later than 20 days. Peak serum levels of R24 were related to dose and ranged from a mean of 0.9 micrograms/mL at the lowest dose level (1 mg/m2/d) to 44 micrograms/mL at the highest dose (50 mg/m2/d). The amount of R24 reaching tumor sites corresponded to the dose administered, and R24 could be detected in tumors as late as 30 days after finishing treatment. Inflammation at tumor sites was observed during treatment. Biopsies of tumors taken before, during, and after treatment revealed that R24 induced deposition of complement components, increased numbers of mast cells with mast cell degranulation, and infiltration of T lymphocytes. These results suggest that treatment with R24 can produce a localized inflammatory response at tumor sites that is capable of producing tumor regression.

Central venous device-related infection and thrombosis in patients treated with moderate dose continuous-infusion interleukin-2

“…21,22 Ch14.18 antibody was developed by Stephen D. Gillies (Fuji Immunopharmaceutical Corporation, Lexington, MA) and provided by the NCI-BRMP. R24 antibody is a murine monoclonal antibody that detects the GD3 ganglioside expressed on melanoma, gliomas, and soft tissue sarcomas 23,24 and was provided by the NCI-BRMP.…”

Immunity to melanoma: unraveling the relation of tumor immunity and autoimmunity

“…Although GD3 is the most highly expressed ganglioside and can be upregulated more than 10 000-fold in the process of malignant transformation (Albino et al, 1992), its immunogenicity is low (Ritter et al, 1991). However, passive transfer of antibodies against GD3 in patients with melanoma can induce major responses, even in large visceral tumors (Houghton et al, 1985;Vadhan-Raj et al, 1988).…”

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

“…1,3 Direct complement-mediated cytotoxicity and ADCC have been predicted to follow direct dose-dependent patterns. 12 Doses of R 24 up to 800 and 1200 mg/M 2 over 6 -8 days have been reported to induce doselimiting toxicity, 11 including allergy, capillary vascular leak syndrome, and lymphopenia and serum sickness but not improved therapeutic results.…”

“…For treatment, R 24 was diluted in physiologic saline with 5% human serum albumin and administered intravenously as a 192-hour infusion. The following antibodies were used for immunohistologic studies: Anti-gp240, a monoclonal antibody directed against a high molecular weight proteoglycan associated with melanoma obtained from Hybritech (San Diego, CA); Leu4 (anti-CD3), Leu3a ϩ 3b (anti-CD4), Leu2a (anti-CD8), anti-HLA DR, DP, and DQ purchased from Becton Dickinson (San Jose, CA); control mIgG 1 and mIgG 3 were purchased from Tago (Burlingame, CA) and Sigma (St. Louis, MO), respec-tively. Factor VIII-related antigen and fluorescein isothiocyanate (FITC)-labeled antihuman complements C1q, C3c, C4, C5, and rabbit Ig control were purchased from Dako (Carpinteria, CA).…”

“…This antibody has demonstrated tumor binding in vitro that corresponds with its localization in vivo; 1 complement-dependent cytotoxic activity in vitro 2 has been associated with the observation of tissue deposition of complement components. 1 In addition, several IgG 3 MoAbs against the GD3 ganglioside have been shown to mediate antibody-dependent cellular cytotoxicity (ADCC) through interaction with large granular lymphocytes, 1,3,4 and to induce lymphocyte proliferation. [5][6][7] The current investigation was conducted as a dose-seeking clinical and immunologic Phase I (Phase IB) evaluation of R 24 .…”