RE: Cell mutations3 Nov 2022 16:09
Havelot,
Firstly, my condolences for your loss. Even with the length of time passed, it doesn't make the loss any less sad. Secondly, what a great question.
So there are a number of things to think about when it comes to Modi-1. Firstly, it isn't a single therapy, but a three in one hit. Modi-1 consists of three peptides (short fragments of protein) from two seperate proteins. The first is vimentin, a cytoskeleton protein which is used by normal cells to maintain their shape and internal organisation. The second is from a protein called alpha-enolase. This protein is a key enzyme involved in a metabolic process called glycolysis which cells use to generate energy. In modi-1, two peptides come from vimentin and the third comes from a-enolase.
Now we look at the tumour. These are metabolically stressed - with low oxygen levels and nutrient deficiency. The cell is basically fighting to survive, so to do so the cells start consuming their own proteins in a process known as autophagy. Therefore the cancer cell starts digesting it's normally functioning proteins (including vimentin and alpha enolase) to survive, and in doing so generates energy for survival but also random fragments of protein.
These random fragments of protein can be modified by other enzymes found within the cell. In this case, the vimentin and enolase peptides are modified by an enzyme known as peptidylarginine deaminase (PAD). Now we get technical. PAD converts a peptidyl arginine to peptidyl citrulline. So think of it simply as the enzyme adding a red flag on that peptide in a specific place. PAD will do this without external input. Every time it sees an arginine it will convert it to citrulline i.e. adding a red flag.
So let's take a step back and look at the cancer cell. It is battling to survive, it has a need for a cytoskeleton and energy generation. Therefore there is no pressure to mutate either of these. PAD also has no external pressure to mutate either, it's happy doing it's job. But together, the cell is basically a red flag producing factory. Even better, it's producing three separate red flags.
So unlike a target that say an antibody, CAR-T or small-molecule would traditionally target, the cancer cell doesn't have a huge selection pressure to down regulate or mutate these. This presents a problem for the cancer cell as it cannot easily beat Modi-1.
Now the additional benefit here is that because Modi-1 targets three different peptides, even if the cancer mutated the vimentin/a-enolase and lost an arginine (meaning it lost a target for PAD to citrullinate), the likelihood of it mutating three separate sites on two separate proteins is probably minimal.
Fundamentally moditope is less about targeting individual proteins, but instead targeting metabolic pathways and their byproducts. This also has the benefit of it being patient agnostic (and quite possibly also cancer agnostic).
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