Technology platforms
Hubro Bioscience has aquired the established technology platforms of Hubro Therapeutics AS. One platform covers proprietary vaccines for prevention of cancer. The vaccines are based on peptides corresponding to neo-antigens resulting from frameshift mutation characteristically present in cancers associated with genetic microsatellite instability (MSI). The vaccine technology can also be developed as proprietary DNA and RNA constructs.
Hubro Therapeutics’ vaccines induce cancer specific T cells. T cells that recognize peptide epitopes processed from neo-antigens, and that is displayed by dendritic cells and transformed cells, can be stimulated to protect against progression of cancer.
The second technology platform covers proprietary tests for detection of bio-markers early occuring in liquid biopsies of hereditary cancers as well as sporadic cancers associated with MSI and Lynch Syndrome in liquid biopsies. The bio-markers might also be used rapid and simple tests foor confirmation of MSI and elegibility for check point inhibition (CPI) immunotherapy for cancer.
Frameshift mutations
Frameshift mutations, the hallmark of MSI related cancers, are 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, neoantigen, with a completely different amino acid sequence when 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 anticancer T cellular immune responses. Frameshift mutant TGFβR2 is present in 44% of MSI related cancers and particularly in more than 77% of MSI-H colorectal cancer (Maby P. et al. Cancer Res; 75(17) September 1, 2015 (3446 – 3455)) and 80% of MSI-H stomach cancer (Cortes-Ciriano I et al 2017; NATURE COMMUNICATIONS|8:15180| (2017)). Over 90% of patients with familial hereditary colorectal cancer (Lynch Syndrome) have TGFβR2 frameshift mutation (Pinheiro M et al, British Journal of Cancer (2015) 113, 686–692).
| Cancer | MSI | Annual incidence (MSI) | |
| Europe + N. America | Asia | ||
| Colorectal (CRC) | 15-20% | ≈100 000 | ≈140 000 |
| Endometrial (EC) | 28% | ≈50 000 | ≈40 000 |
| Stomach (SC) | 22% | ≈35 000 | ≈170 000 |
Diagnosing the underlying cause of MSI
The underlying cause of progression of MSI cancers is a deficient mis match DNA repair MMR machinery (dMMR). dMMR can be diagnosed. Lynch syndrome is condition where dMMR is inherited from one or both parents and is a condition with a life-time high-risk of cancer. Therefore, these vaccines have a potential in prophylactic settings for protection against development of 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% (Cortes-Ciriano I et al 2017; NATURE COMMUNICATIONS|8:15180| (2017)). The major risk factor for development of hereditary MSI cancers is dMMR as in Lynch Syndrome. The prevalence of Lynch Syndrome is estmated to be 1 in 273 subjects of the general population.
Lynch Syndrome - life-time increased risk of cancer
| Cancer | Population risk | MLH1 and MSH2 | MSH6 | PMS2 | |||
| Risk | Mean age of onset | Risk | Mean age of onset | Risk | Mean age of onset | ||
| Colon | 5.5% | 55-80% | 44-61 | 10-20% | 54 | 15-20% | 61-66 |
| Endometrial | 2.7% | 25-60% | 48-62 | 16-26% | 55 | 15% | 49 |
| Stomach | <1% | 1-13% | 56 | <3% | 63 | 70-78 | |
| Ovary | 1.6% | 4-24% | 42.5 | 1-11% | 46 | 42 | |