So it seems the American "traders", very different from investors, have got hold of CAT. They ran it up as far as they could on momentum and then started to dump when they hit a brick wall at 14 pounds. I hate this kind of market volatility...it always stinks of traders who didn't even bother to research the company.
In the meantime, I've been doing more homework. It turns out that CAT's antibodies to TNF and TGF both have binding constant in the range of 10 to the minus 10. I don't think ABGX or MEDX could possibly make a mAb with a binding affinity sufficiently higher such that clinical efficacy is improved (see below for evidence). In any case, the literature is starting to recognize that the clinical bioactivity of an antibody is not soley determined by its binding affinity for its cognate ligand. Other factors such as isoelectric point, biological half life, etc. play critical roles in determining bioactivity. In fact, recent evidence suggests that low affinity antibodies can be highly biologically potent. In any case, after speaking with CAT again, I am now convinced that the large size of their Ig library (which by the way is derived from donors of many different types, eg. adult, enfant etc.)
facilitates the generation of mAbs with very high affinity and bioactivity. CAT also employs in vitro mutagenesis and selects their mAbs based on bioactivity and not just affinity.
It appears, then, that negative selection against autoreactive B cells is not complete (not a new idea) and in fact somatic hypermutation occurs against self antigens(this is a new idea). Nonetheless, as an immunologist who studies immunoregulatory pathways I have noted that animals (and humans) with Th1 mediated autoimmunity invariably do better if they produce autoantibodies. This phenomenon has been the basis for the model that low affinity autoimmune Th2/3 cells that escape thymic selection are necessary for protection from Th1 mediated autoimmunity. I can discuss this in more detail later if requested. Proof of the bioactivity of CAT's mAbs was presented this week in London. Unlike Enbrel which relieves the symptoms of RA at high doses and results in a rebound after drug withdrawl, CAT's anti TNF mAb is effective at comparitively low doses and although symptoms of arthritis recurr after withdrawl, no rebound is observed. To my knowledge this is the first anti TNF reagent that can make this claim. The anti TGF story is just as nice. It appears to be very effective at preventing fibrosis. I've read papers on the use of anti TGF mAbs for glaucoma (Invest Ophthalmol Vis Sci 1999 40(10):2225) neural scarring (Eur J Neurosci 1999 11(7):2367, Laryngoscope 1999 109(4):631), and pulmonary fibrosis (Thorax 1999 54(9):805), and the the results seem very encouraging. Compared to Medarex which has picked anti CTLA-4 as their first mAb and bispecific mAbs which bind tumour antigens and macrophages as their second product, I think CAT has a much better chance of acheiving good efficacy without encountering major side effects. They have been quiet and calculated about their antigen targets...I think this is a mark of a well run company which is not driven only by the guys in businessmen who eat, drink and sleep money. |
