Accession Number:

ADB264611

Title:

Stimulating CTL Towards HER2/neu Overexpressing Breast Cancer

Descriptive Note:

Final rept. 30 Sep 1997-29 Sep 2000

Corporate Author:

NORTH CAROLINA UNIV AT CHAPEL HILL

Personal Author(s):

Report Date:

2000-10-01

Pagination or Media Count:

53.0

Abstract:

We proposed to establish an approach by which tumor cells are eradicated through selective induction of CD8 T cells specific for a protein overexpressed in many adenocarcinomas. A peptide derived from HER-2neu HN654-662, GP2 stimulates cytotoxic T lymphocytes CTL that lyse primary tumors from ovarian or breast cancers. It has been proposed that the poor immunogenicity of GP2 is due to poor binding to HLA-A2.l. Our data demonstrate GP2 is an extremely poor HLA-A2.l binding peptide. Furthermore, modifications to anchor residues, predicted to improve binding, do not significantly increase affinity. We have determined the structure of A2GP2 and show that the center of the peptide is disordered. Combinations of anchor substitutions and another substitution V5L that had improved affinity show reduced affinity compared to the individual substitutions. This indicates that there are significant interactions between the different residues bound to HLA-A2.l. Individual substitutions at positions 3, 5, 6 and 7 do not significantly increase affinity. Transgenic A2Ksuper script b mice do not generate a response to GP2 either as peptide or bound to dendritic cells. Some of the variants of GP2 do generate a CTL response, but do not recognize GP2-pulsed targets well. Mice doubly transgenic for A2Ksuper script band HER-2neu MMTV promoter generate spontaneous tumors around 5 months of age. Peptide immunization can induce CTL responses towards HER-2neu peptides presented by the tumor.

Subject Categories:

  • Biochemistry
  • Medicine and Medical Research
  • Crystallography
  • Nuclear Physics and Elementary Particle Physics

Distribution Statement:

APPROVED FOR PUBLIC RELEASE