The Modi-2 vaccine exploits a second post-translational modification, stimulating the production of CD4 T cells using tumour-associated peptide epitopes in which the lysine residues are converted to homocitrulline. This change occurs via a process known as carbamylation, leading to a change in molecular charge which, in turn, alters antigenic properties and can result in the generation of unique T cell epitopes.
Scancell has identified homocitrullinated epitopes derived from several proteins, including vimentin, aldolase, cytokeratin 8, immunoglobulin binding protein (BiP), nucleophosmin (NPM), α-enolase, β-catenin and heat shock protein (HSP-60), all of which generate potent T cell responses in preclinical models. Evidence exists for all of these proteins having a link to a wide range of cancer types:
- Aldolase (like α-enolase) is a glycolytic protein which is highly expressed in a number of cancers and upregulation of the aldolase gene has also been linked to poor prognosis in colon cancer, renal cell carcinoma and colorectal cancer.
- Keratins are the largest family of intermediate filament proteins and have a wide tissue distribution, multiple functions and disease associations. Cytokeratin expression, along with the cytoskeletal protein vimentin, results in increased invasion and metastasis in breast cell carcinomas and melanomas.
- BiP is preferentially expressed on the surface of stressed cancer cells, where it is involved in the regulation of critical oncogenic signalling pathways.
- NPM plays a variety of roles in cellular metabolism and overexpression of NPM has been reported in multiple human cancers including those of the pancreas, prostate, liver, colon, stomach and thyroid.
- β-catenin is a proto-oncogene and mutations are commonly found in a variety of cancers, including primary hepatocellular carcinoma, colorectal cancer, ovarian carcinoma, breast cancer, lung cancer and glioblastoma.
- High expression levels of HSP60 have been noted in several cancers; it favours the survival of certain types of tumour cells and, in some cases, may be essential for tumour-cell growth.
For the first time, Scancell has been able to demonstrate that anti-carbamylated T cell responses can be stimulated against these proteins and that these can mediate potent anti-tumour therapy. Work is underway to characterise and select specific homocitrullinated peptides for clinical development that have the potential to address different cancer indications to Modi-1, including tumours with a particularly immunosuppressive environment.