The MAGE-A family of proteins comprises a highly homologous 12-member group of antigens with an unknown role in normal physiology. Recent data suggests a central role for MAGE-A proteins in early events of oncogenic transformation, tumor invasion, and metastasis, and presence of MAGE-A is associated with poor patient outcome. MAGE-MHC-1 complexes are broadly exposed on many cancers including chemo- and radiation-resistant types such as malignant melanoma, pancreas tumors, multiple myeloma and non-small cell lung cancer, but not by healthy tissues (except testis that does not express MHC).
It has been suggested that MAGE-A expression is mandatory for tumor cell survival. MAGE-A proteins are continuously degraded in the cellular cytoplasm of tumor cells and presented as 8 to 9 amino acid long peptides by MHC-1 on the cell surface to killer T-cells (Figure 1). Killer T-cells may recognize the MAGE-MHC-1 peptide complex on tumor cells as non-self, and exert their immune regulatory functions such as tumor cell kill and production of immune stimulatory molecules. Each human individual may express up to six MHC-1 alleles (one HLA-A, -B, and -C allele from each parent). Because individuals express different MHC-1 alleles treatment with AIMs, each targeting one MHC-1 allele, requires the generation of multiple AIM molecules to cover the global population, but it also allows for alternating treatments when a MHC molecule is down-regulated.
The high homology between the twelve MAGE-A proteins allows for identification of 8-9 amino-acid peptides that are shared by multiple members of the MAGE-A family. These multi-MAGE-A peptides are presented by MHC-1 and thus allow multi-targeted therapy of tumors with highly heterogeneous expression of individual MAGE-A proteins in individual cells.