Ii-Key/MHC class II epitope peptides as helper T cell vaccines for cancer and infectious disease
Nikoletta L. Kallinteris, Douglas Powell, Catherine E. Blackwell, MaryBeth Kim, Xueqing Lu, Shuzhen Wu, Robert E. Humphreys, Minzhen Xu, and Eric von Hofe
Antigen Express, Inc., 100 Barber Ave., Worcester, MA 01606-2478
TABLE OF CONTENTS
- 1. Abstract
- 2. Introduction
- 3. Discovery of the function of the Ii-Key segment of the Ii protein to regulate tightness of binding of antigenic peptides into MHC class II molecules
- 3.1. Logic and experimentation leading to potent Ii-Key/MHC class II epitope hybrid vaccine peptides
- 3.2. Hypothesis on the mechanism of action of Ii-Key/MHC class II epitope hybrid peptides
- 4. Do Ii-Key motifs occurring naturally in antigenic proteins regulate selection among their MHC class II epitopes?
- 5. Design of Ii-Key/melanoma gp100 (46-58) MHC class II hybrids
- 5.1. Algorithm and rationale for the design of Ii-Key/MHC class II epitope hybrid vaccine peptides
- 5.2. Preference for polymethylene chain versus residues of the native sequence N-terminal to the P1 site residue
- 5.3. Protease protection
- 5.4. Enhanced solubility
- 5.5. Limiting autorelease of hybrids by use of shorter spacers
- 6. Use of Ii-Key MHC Class II epitope hybrids as anti-cancer helper T cell vaccines
- 6.1. Ii-Key enhances in vivo priming of CD4+ T cells to the gp100(46-58) epitope in DR4 transgenic mice
- 6.2. Ii-Key enhances in vitro priming of CD4+ T cells by the Tyr(365-381) melanoma epitope in normal donor lymphocytes
- 6.3. Ii-Key enhances in vitro priming of CD4+ T cells by the promiscuous HER-2/neu (776-790) epitope in normal donor lymphocytes
- 6.4. Conclusions from experimental studies
- 7. Clinical trials with Her-2/neu MHC Class II epitope peptides
- 7.1. T helper stimulation and cancer immunotherapy
- 7.2. Active HER-2/neu immunotherapy: limitations of vaccinating with only MHC class I epitopes
- 7.3. Active peptide immunotherapy for melanoma
- 8. Summary and Perspective
- 9. Acknowledgement
10. References
1. ABSTRACT
Potent MHC class II antigenic peptide vaccines are created by covalently linking the N-terminus of a MHC class II epitope through a polymethylene bridge to the C-terminus of the Ii-Key segment of the Ii protein. Such hybrids enhance potency of presentation in vitro of the MHC class II epitope about 200 times relative to the epitope-only peptide. In vivo, as measured by IFN-γ ELISPOT assays, the helper T cell response to vaccination is enhanced up to 8 times. The design of such hybrid vaccine peptides comes from insight into the mechanism of action of the Ii-Key motif within the Ii protein, in regulating antigenic peptide binding into the antigenic peptide binding groove of MHC class II molecules. Here we present the logic and experimental history of the development of these vaccine peptides, with particular attention to the hypothesized mechanism of action. Methods for the design and testing of these peptides are presented. Experience in developing peptide vaccines for immunotherapy of cancer is reviewed, focusing on the clinical potential of Ii-Key/MHC class II epitope hybrids.
