Immunogenicity of synthetic peptides related to the core peptide sequence encoded by the human MUC1 mucin gene: Effect of immunization on the growth of murine mammary adenocarcinoma cells transfected with the human MUC1 gene

Abstract

The immune response of CAF1 mice to various synthetic peptides (SP) related to the amino acid sequence (PDTRPAPGSTAPPAHGVTSA) of the tandem repeat of the MUC1 human breast mucin core peptide was evaluated. The most immunogenic preparations of the synthetic peptides were those conjugated to keyhole limpet hemocyanin (KLH) or clustered in a dendritic multiple antigenic peptide (MAP-4) configuration. The mice were immunized subcutaneously with synthetic peptides emulsified in RIBI adjuvant, employing various immunization protocols. Equivalently high IgG responses were induced using SP-KLH conjugates (GVTSAPDTRPAPGSTA-KLH) or an SP--MAP-4 chimeric configuration (SP1-6), which also included a universal malarial CST-3 T-helper epitope (SP1-6 = SAPDTRPAEKKIAKMEKASSVFNVVNS--MAP-4). These IgG antibodies bound both the appropriate MUC1 synthetic peptides and the cell surface expressed MUC1 mucin on murine mammary cells that had been transfected with the human MUC1 gene and a human breast cancer cell line that expresses cell-surface MUC1. A MAP-4 molecule, which included the entire 20-amino-acid sequence of the MUC1 tandem repeat (SP1-5 = PDTRPAPGSTAPPAHGVTSA-MAP-4) induced a poor IgG response. In contrast, all three types of molecule: SP-KLH, SP1-6 and SP1-5, were found to be good immunogens for the induction of specific delayed-type hypersensitivity (DTH) reactions measured using either synthetic peptides or MUC1-transfected cells. In addition, immunization with irradiated MUC1-transfected cells induced strong DTH reactions measured using synthetic peptides that expressed the PDTRP sequence, which has been shown to be, or to overlap, a T cell epitope in humans and a B cell epitope in mice. Finally, it was demonstrated that synthetic MUC1 peptide "vaccines" could be used both prophylactically and therapeutically to inhibit the growth of MUC1-transfected tumor cells and prolong the survival of tumor-bearing mice.

Lewis Y Antigen as a Target for Breast Cancer Therapy

“…These data further suggest that the generated sera is minimally binding to normal tissues while displaying strong binding to tumor tissues that over express histoblood group related carbohydrates. These data suggest that even though this serum reacts with common structural features of MCP and LeY, the presentation of related carbohydrate forms on tissues are affected by the carrier molecules to which they are attached as previously suggested (39) or the density of expressed carbohydrate.…”

Th2-dominated antitumor immunity induced by DNA immunization with the genes coding for a basal core peptide PDTRP and GM-CSF

“…Our data are consistent with earlier reports that the PDTRP core epitope of human MUC-1 was immunogenic in mice, and PDTRP-specific immune responses induced with a peptide-based vaccine could delay tumor growth. Ding et al 45 demonstrated that peptide-based PDTRP vaccination with a proper adjuvant or Th epitope could induce strong PDTRP-specific antibody and DTH responses, which correlated directly with prolonged survival of tumor-bearing mice. Using a DNA vaccine approach, Kontani et al 46 showed that a MUC-1-based DNA vaccine induced a protective antitumor immunity in naı¨ve mice, but the efficacy of the DNA vaccine in tumorbearing mice strictly depended on the induction of cellmediated immune responses and coinjection of activated DCs.…”

Lung Cancer Immunotherapy

“…They exhibit unique glycosylation patterns, making them tumor-specific immunogens. 34 In a phase I clinical trial using MUC1 peptide in stage III/IV NSCLC, 35 safety and tolerability of this agent was established. Five of 12 patients (42%) had immunologic responses, and 4 of 12 patients (33%) achieved stable disease.…”