TRIL
Thx for the link i remember seeing this but was busy at the time to comment, and I think it's worth of some discussion given the rather surprising finding from the standford trial to date that "Regarding safety, preclinical models reported low-grade anemia associated with anti-CD47 agents. However, this has not yet been observed in the phase I data". We all know TRIL is hoping their drug in part is differentiated from CD47 antibodies on better hematological safety. It could just be that the stanford drug just hasn't reached therapeutic dose yet, but that would be surprising given how long it has been in the clinic - i definitely would have thought dose escalation is done by now. If anyone has thoughts I'm all ears since i don't really know why anemia wouldn't be a side effect (and a prominent one at that). They are dosing up to twice weekly in the AML trial so there does seem to be an "antigen sink" effect. Celgene purportedly has an antibody that doesn't cause RBC agglutination like other MAbs yet they altered their exclusion criteria to include a longer period of transfusion independence so it suggests they did see some heme tox.
One point that is worth noting is that standford's drug is an IgG4, which has far less ADCC than TRIL's fusion using an IgG1 construct. In fact they specifically chose IgG4 to minimize toxicity becuase of the weaker Fc activity. This contrasts with TRIL, which went with IgG1 subtype in the clinic. TRIL had looked at both IgG1 nad IgG4 constructs and showed better single agent activity with the IgG1 (links should be on their website). This flips the script somewhat now in that TRIL may not have better heme tolerability to stanford, but may do better on efficacy based on using a drug w stronger Fc activity, espeically now that there is a suggestion the stanford drug is binding to CD47 on RBCs but not killing them
