$heff's $tation of $tocks & $olid DD

[ronpopeil]

dewophile Friday, 05/20/16 06:22:25 PM
Re: NY1972 post# 201496
Post #
201498
of 201498 Go
Quote:
If calreticulin is expressed on tumor cells and 1 mg/Kg anti CD47 mAb has achieved target saturation, why the clinical benefit is so underwhelming>

The 1 mg/kg dose resulted in a mean RBC CD47 receptor occupancy of 91% ± 3% [95% CI 86 – 93%], indicating target saturation with no G3 anemia, and was selected as the Priming Dose.


According to TRIL there are >100,000 fold more CD 47 receptors on RBCs than on tumor cells. So it could be that 91% saturation is just not enough and the remaining 9% of RBCs is enough to cause substantial off target drug deposition. So the higher dose cohorts currently enrolling could see more of an effect. It's also very small numbers so far

It could also be that their construct is not effective enough. Read the stanford paper they went with an IgG4 to minimize toxicity. but that comes at the expense of efficacy. I know this group talks up calreticulin as a prophagocytic stimulus on tumors so in theory all you need to block is CC47 but TRIL (and others) have shown you need effector function for efficacy (at least as monotherapy). TRIL has data showing zero efficacy in vivo with an SIRP-control Fc, mild efficacy with IgG4, and much better efficacy with IgG1 Fc. They developed both IgG constructs and went with IgG1 for their lead. Stanford couldn't afford to do that due to off target binding

It could also be that you do need another agent like PD-1 inhibitor for optimal efficacy in humans, as suggested by the other stanford group spinoff in the publication I posted in response to your last question

Lastly it could be that the target is a total dud. If that's the case TRIL goes to under cash,. But realize this is setting up as the ultimate boom or bust scenario bc everything TRIL has suggested about the stanford drug seems to be true so far (yes it is early). Celgene has also gone on record saying their drug has some of the best preclinical data they have seen (and they know a thing or two about blood cancers), but there may be some dosing and tox issues related to thrombospondin - something TRIL's drug should also in theory avoid. So talk by TRIL of having potential best in class very well may be the case. If that unfolds then the skys the limit TRIL could be 2000+ a share (think ibrutinib's valuation). There may only be a 10% chance of this scenario unfolding, but if it does it's a ride i plan to be on