An Anti-Idiotype Vaccine Elicits a Specific Response to N-Glycolyl Sialic Acid Residues of Glycoconjugates in Melanoma Patients

Abstract

We generated the 1E10 γ-type anti-idiotype mAb (Ab2) specific to an Ab1 mAb able to react specifically with N-glycolyl-containing gangliosides and with Ags expressed on human melanoma and breast carcinoma cells. This Ab2 mAb induced an Ab response in animal models sharing immunochemically defined idiotopes with the Ab1. The treatment of tumor-bearing mice with 1E10 mAb induced a strong antitumor activity. A clinical trial was conducted in 20 patients with advanced malignant melanoma. Patients were treated with six intradermal injections of aluminum hydroxide-precipitated 1E10 anti-Id mAb given at 2-wk intervals. Sixteen of the 17 patients who received at least four doses of the anti-Id vaccine develop Ab3 Abs capable of inhibiting Ab2 binding to Ab1 (Ab3Id+). In contrast to the incapacity of 1E10 mAb to generate Ab3 Abs with the same antigenic specificity as the Ab1 mAb in mice, a very specific and strong Ab3 response against N-glycolyl-containing gangliosides was induced in 16 patients (Ab3Ag+). No evidence of serious or unexpected adverse effects has been observed in this clinical trial. 1E10 anti-Id vaccine was safe, well tolerated, and immunologically effective, with most patients being able to generate a specific immune response against 1E10 and Neu-glycolyl-GM3 ganglioside.

Characterization of the Antibody Response against NeuGcGM3 Ganglioside Elicited in Non-Small Cell Lung Cancer Patients Immunized with an Anti-Idiotype Antibody

“…This Ab2, named 1E10 (17), was generated from the immunization of BALB/c mice with P3, an idiotypic Ab (Ab1) that recognizes NeuGc-containing gangliosides, sulfated glycolipids, and Ags present in different human tumors including those from the lung, and which contains a regulatory Id according to Bona's concept (18 -24). Preparations containing 1E10 mAb were able to induce antitumor effects against lung metastases in murine models, and phase I clinical trials have proven the safety and immunogenicity of 1E10 Id vaccination in melanoma and breast cancer patients (20,25,26). From these latter studies, high titer Ab responses to NeuGc-containing gangliosides were measured in the sera of cancer patients.…”

Lonely killers

“…[58][59][60][61]63 A positive correlation between the development of such antibodies and patient survival was found. 63 Despite the lack of direct cytotoxicity by P3 mAb, 66 the antibodies generated by the anti-idiotypic vaccine were able to directly kill GM3(Neu5Gc)-expressing cells.…”

“…GM3(Neu5Gc) is a ganglioside whose expression has been detected in some human tumors, including breast and melanoma. 53,55,56 Several therapeutic strategies have been developed against this target, 14 e.g., vaccines (ganglioside-based 57 and antiidiotypic [58][59][60][61][62][63] ) and mAbs. 55 14F7 mAb is specific for this ganglioside and unable to bind its N-acetylated (Neu5Ac) counterpart.…”

Anti-idiotype antibodies in cancer treatment

“…Finally, other phase-II clinical trials based on anti-Id mAb-based vaccines, whose encouraging results need further confirmation in controlled studies, are those respectively utilizing the so-called TriGem formulation (Lutzky et al, 2002) and the 1E10 g-type, anti-Id mAb, whose mimicry concerns N-glycosyl-containing gangliosides as well as other antigens expressed on human melanoma and breast carcinoma cells (Alfonso et al, 2002). In both cases, anti-Id mAb-based vaccination elicited strong and specific humoral responses directed against all antigens involved in the mimicry pattern.…”