Hi BarrelSitter,I work in the field and I think what you have...

Hi BarrelSitter,

I work in the field and I think what you have proposed, while it sounds logical, probably isn’t the way they have set up their manufacturing process(es).

It IS possible to make smaller fragments of an antibody, by performing a specific cleavage using enzymes called proteases. Historically the ones used for antibodies are papain or pepsin, which cleave the bit of the antibody that recognises the target (called Fab, from “fragment, antigen-binding”) from the rest of the molecule. On a small-scale this works pretty well, but to scale up isn’t desirable, as: (1) scaling up the proteases can get expensive and (2) you then need to remove them so that they don’t have prolonged exposure to the product and potentially cause unwanted cleavage elsewhere in the product.

As a result, it’s preferable to try to produce your product so it only contains the bit you want and doesn’t require cleavage as described above. Having a quick look at the abstract of the relevant paper on the Patrys website (Rattray et al, 2018) it looks like they have engineered PAT-DX1 this way. The molecule contains two copies of the antigen-binding region tethered together by a linker. That means there isn’t any of the rest of the molecule (called Fc, from “fragment, crystallisable”) to get rid of. The downside of that approach is that by removing the Fc domain, the product can no longer be purified by Protein A affinity resin, which is one of the most common and robust ways of purifying mAbs.

I would imagine that as an intact monoclonal antibody, PAT-DX3 looks like a much more standard molecule and would be subject to more standard mfg processes. So with any luck the production of that for tox and clinical supply will run quite a bit smoother, and wouldn’t share the same challenges recently reported for PAT-DX1. I would add the caveat here that having worked with various mAbs through my career, they all behave in their own unique way, so it may have its own different issues!

Either way it’s not uncommon for this type of thing to happen, especially when working with external partners. I’ve been on the receiving end of some dramas working with CDMOs during roles in both small and big biotech. Disappointing to have an unexpected delay, but it’s all part of the process of working with early stage assets.