Our vaccines are based on peptides corresponding to neoantigens resulting from frameshift mutation characteristically present in cancers associated with genetic microsatellite instability (MSI). The underlying cause of MSI is known and can be diagnosed. Therefore, in addition to treatment of cancer, our vaccines can also have a potential in the prophylactic setting for protection against development MSI related cancer. The vaccines are designed to entail nested epitopes for both CD4+ and CD8+ T cells.

MSI is observed across a range of cancers and is particularly prominent in colorectal cancer, stomach cancer and endometrial cancers with a frequency of 15-28%. The major risk factor for development of hereditary non-polyposis colorectal cancer is MSI.

Frameshift mutation

Frameshift mutation, the hallmark of MSI related cancer, is caused by defects in the DNA mismatch repair (MMR) machinery. It occurs in genes with stretches of short tandem DNA repeats (microsatellites) and is constituted by nucleotide deletion and/or insertion in the micro satellite. The frameshift mutation creates a shift of codons for protein expression, resulting in a mutant protein (neo-antigen) with a completely different amino acid sequence as compared to the normal protein expressed by the wild type gene. Neo-peptide epitopes from frameshift mutant protein sequences are foreign to the immune system of the host and are therefore potentially strong antigens that can be used as vaccines for activating specific anti-cancer T cellular immune responses. 

Target mutations and vaccines

The mutation signature of different cancers is often different from each other. By focusing on the most common and shared frameshift mutations across MSI cancers Hubro Therapeutics has established a proprietary neo-peptide technology platform. The core neoantigens of our proprietary technology platform cover frameshift mutation in TGFBR2, KIAA2018, SLC22A9, ASTE1 and TAF1B.

The neo-peptide technology platform provides a solid basis for development of both single-target vaccines and multi-target vaccines.

Our lead candidate vaccine FMPV-1 targets frameshift mutation in the transforming growth factor b receptor 2 gene (TGFBR2). Frameshift mutant TGFbR2 is present in 44% of all MSI cancers and particularly in more than 60% of MSI-H colorectal cancer and 80% of MSI-H stomach cancer. Over 90% of patients with familial hereditary colorectal cancer have TGFbR2 frameshift mutation.