Tumour-associated glycopeptide antigens and their modification in anticancer vaccines - Carbohydrate Chemistry: Chemical and Biological Approaches - page 506

Tumour-associated glycopeptide antigens
and their modification in anticancer
vaccines
Sebastian Hartmann, Bj ¨ rn Palitzsch, Markus Glaffig and
Horst Kunz*
DOI: 10.1039/9781849739986-00506
Glycopeptide antigens are obtained by solid-phase glycopeptide synthesis using
fluorenylmethoxycarbonyl-(Fmoc)-protected O-glycosyl threonine and serine building blocks
representing the tumour-associated mucin carbohydrate antigens. Conjugation of the synthetic
mucin glycopeptide antigens with T-cell epitope peptides and/or immune stimulating lipo-
peptides affords fully synthetic two- and three-component vaccines useful for immunization of
mice. Conjugates of the synthetic tumour-associated glycopeptide antigens with carrier pro-
teins, in particular with tetanus toxoid, proved to be potent antitumour vaccines inducing high
titres of IgG antibodies, which strongly bind to breast tumour cells. Mimics of the carbohydrate
antigens within these glycopeptides also result ine cientvaccinesaslongasthecarbohydrate
structure remains closely related to the natural tumour-associated carbohydrate antigen.
1 Introduction
Most proteins found in membranes of mammalian cells are glycosylated.
This holds, in particular, for the mucins which are expressed by most
types of epithelial cells, e.g. in the salivary gland, breast, liver, pancreas
etc. 1 The glycans of glycoproteins not only influence physicochemical
properties of these macromolecules and protect the proteins from
enzymatic degradation, but also play key functions in processes such as
cell adhesion, cell differentiation and cell recognition.
Therefore, it is not surprising that the glycan pattern of the glyco-
proteins from tumour cells were found distinctly different from those of
healthy cells. 2 The existence of tumour-associated carbohydrate antigens
(TACA) raises the attractive prospect of developing antitumor vaccines.
The identified carbohydrate motifs, as for example the Thomsen-
Friedenreich antigen 2, 2 built into a synthetic glycopeptide vaccine, 3 do
not induce a suciently tumour-selective immune response in mice. 4
The obtained results, however, strongly suggest that not only the tumour-
associated carbohydrates, but also the peptide sequences are involved in
epitopes which allow an immunological differentiation between normal
and tumour cells. On the basis of these observations, the tumour-
associated mucins, in particular mucin MUC1, also referred to as
episialin, 5-8 have attracted increasing attention as target structures for the
construction of synthetic antitumour vaccines. MUC1 is strongly over-
expressed on a number of epithelial tumours. It is a large membrane-
anchored glycoprotein and reaches far (W100 nm) into the extracellular
space. In its extended extracellular part it contains a domain consisting of