MUC1-derived glycopeptides for the development of a multi-epitope anti-tumour vaccine
Reference Number TO 03-00043C
The Challenge
The discovery of immunogenic tumour-associated antigens represents the basis for all cancer immunotherapy concepts and the development of anti-tumour vaccines. The human mucin MUC1 is one of the most established epithelial tumour markers and currently considered as one of the most promising immunotargets in tumour therapy. MUC1 is a highly glycosylated membrane protein expressed on the luminal side of epithelial cells and inaccessible to human immune responses in healthy tissues. Upon cell degeneration in tumour genesis the apical expression pattern gets lost. In principle subsequent innate CD4- and CD8-related immune responses could occur, but usually are suppressed in tumour patients. Several phase I and II clinical trials on MUC1 have been initiated and improved patient survival could be observed (A). In those either MUC1-specific antibodies, vaccinia virus-based DNA strategies or active specific immunization with the highly immunogenic central tandem repeat peptide carrying the three amino acid motif ‘DTR’ of the extracellular domain of MUC1 were used. These current immunotherapy strategies are based on non-glycosylated peptides or proteins only, since they are known to be more immunogenic than the naturally occurring glycoforms (B), but they suffer from inappropriate specificities of the responses as the target protein is highly glycosylated. However, highly glycosylated antigens may impede intracellular antigen processing and result in reduced immunogenity.The TechnologyThree patent applications hold by Cell Center Cologne (CCC) and the Max-Delbrück-Center Berlin (MDC) relate to several glycosylated peptide derivatives of MUC1, that proof to stimulate CD4- dependent immune responses upon processing (C) and thus provide the basis for the development of an efficient and immunogenic peptide antigen or vaccine for improved in vivo and ex vivo strategies in tumour treatment and prevention. Patent application (I) provides a peptide vaccine with an antigenic and poten-tially immunogenic (D) glycosylation at the threonine residue of the DTR motif. Patent application (II) claims peptide variants of it that in combination with (I) generate a broad spectrum of possible glycosylated and non-glycosylated anti-gens. Patent application (III) covers MUC1 peptides with defined N-terminal structures and glycosylation patterns compatible with intracellular processing of antigens, allowing an optimized antigen design as well as offering methods for producing such peptides. In particular, the combination of the inventions allows the development of a multi-epitope vaccine suitable for the establish-ment of a strong, lasting and comprehensive immune response.Commercial OpportunityExclusive license of one or several patent applications for • development of anti-tumour vaccines (multi-epitope strategy),• peptide antigens for in vivo or ex vivo tumour therapy,• methods for the design of MUC1 peptide vaccines and antigens.Patent situation(I) WO 99/34824, relating patent applications pending in US, EP, JP(II) WO 00/49045, relating patent applications pending in US, EP, JP(III) WO 04/022590, relating patent applications pending in US and EPFurther Reading(A)1) Palmer et al., 2001, Clin. Lung Cancer 3, 49 – 572) Nicholson et al., 2004, Cancer Immunol. Immunother. 53, 809 – 8163) Liu et al., 2004, Proc. Natl. Acad. Sci. USA 101 Suppl. 2, 14567 – 145714) Ramanathan et al., 2004, Cancer Immunol. Immunother. 54, 254 – 2645) Holmberg and Sandmaier, 2001, Expert Opin. Biol. Ther. 1, 881 – 8916) Vaughan et al., 2000, Vaccine 18, 3297 – 3309
(B)
Hiltbold et al., 1999, Cell Immunol. 194, 143 - 149
(C)
Vlad et al., 2002, J. Exp. Med. 196, 1435 – 1446
(D)
1) Hanisch et al., 2003, Eur. J. Immunol. 33, 3242 – 3254
2) Ninkovic and Hanisch, manuscript in preparation
3) Kagan et al., 2004, Cancer Immunol. Immunother. 54, 424 - 430
(general)
1) Karsten et al., 1998, Cancer Research, 58, 2541-2549
2) Karsten et al., 2004, Glycobiology 14, 681 – 692
3) Vlad et al., 2002, J. Exp. Med. 196, 1435 – 1446
4) Hanisch et al., 2003, Eur. J. Immunol. 33, 3242 – 3254
5) von Mensdorff-Pouilly et al., 2005, Glycobiology, in press
