The immune system can both detect and fight cancer; it is known that effective cancer immunity relies strongly on the presence of cancer neoantigens.

 

DNA Mismatch Repair Inhibitors

The DNA mismatch repair ('MMR') pathway provides cells with a highly conserved DNA repair mechanism that plays a critical role during DNA replication, repair and recombination. MMR contributes to the maintenance of genome stability by correcting DNA base mismatches and insertion/deletion (indel) loops that occasionally arise during normal DNA replication. Base pair mismatches occur when incorrect nucleotides are inserted into the newly synthesized DNA strand, and then escape the proofreading function of high-fidelity DNA polymerases. Indel loops more commonly arise in the context of microsatellites - highly polymorphic short repetitive DNA sequences. Alterations in the repeat length of such sequences, referred to as Microsatellite Instability ('MSI'), are used as markers of MMR deficiency ('MMRd') in human cancers.

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Continuous Neoantigen Creation

New ("neo") antigens are abnormal proteins that typically arise from DNA mutations that accumulate during cell proliferation as tumours grow. Neoantigens appear ‘non-self’ to the immune system and many are strong cancer antigens that are immunogenic and subsequently stimulate host immune responses. Cancer neoantigens can provide a very effective ‘target’ for tumour immunity, but suppressive factors such as immune checkpoints as well as an immunologically ‘cold’ tumour microenvironment can restrict the potency of a neoantigen driven anti-tumour response.

Our Pipeline

Building on seminal discoveries and ongoing research of our scientific founders and collaborators, NeoPhore is building a pipeline targeting novel proteins across the DNA mismatch repair ('MMR') pathway.

Our first-in-class MMR modulators will alter the genotype of tumour cells, to elicit increased TMB together with higher neoantigen presentation and tumour immunogenicity, which will reawaken the anti-tumour immune response and leverage sensitivity to immune checkpoint blockade.

 

 

MLH1

Forming part of the MutLα heterodimer with PMS2, MLH1 plays a key role in the MMR process. It is frequently non-functional in colorectal and endometrial cancers associated with MMR deficiency and MSI-H status. Genetic evidence shows that MLH1 loss in tumours correlates with robust immune checkpoint inhibitor ('CPI') sensitivity.

Our goal is to identify and develop MLH1 modulator(s) suitable for clinical studies in H2 2023.

 

 

PMS2

PMS2 is the endonuclease component of the MutLα heterodimer (comprising MLH1) and is key for the DNA repair mechanism. We are developing PMS2 modulators which will transform the tumoral genotype, in order to convert immune “cold” tumours to immune “hot”, thereby conferring sensitivity to CPIs.

Our goal is to identify and develop a PMS2 modulator suitable for clinical studies by 2023.

 

 

Next generation targets

We are actively investigating other MMR pathway targets as part of a wider drug discovery effort.