There was a time when internalizing antibodies were the prime target to use as ACD’s because as they locked onto the antigen, they would get pulled into the cell and of course would take the toxin with them. The way the company tried to get around this issue with CEA, which was not an internalizing antibody, was to us radiation. The company used two, I-132 and Y-90. The market never really got interested in radiolabeled antibodies as shown in BEXXAR and Zevalin, both using the CD20 antibody which is what Rituxan is. BEXXAR used 1-131 and Zevalin used y-90 as the radiation. Both got better responses than Rituxan, but just never became popular to use.
The CL2A linker was designed to overcome the lack of internalization of an antibody, probably CEA being the primary reason. The linker binds to the antibody and the toxin and when it locks onto the antigen on a cancer cell, the linker relaxes its hold on the toxin when it comes into the acidic area surrounding the cancer cell and in the case of SN-38, it gets pulled into the cell. This is more important with CEA than hRS7 as hRS7 is an internalizing antibody, but it’s possible that some hRS7 may not bind firmly enough to get internalized but still releases the SN-38 to do its damage. This is called “Bystander killing”. Still a lot to learn, but we have a good linker in CL2A linker that is not only cleavable, but can carry multiple warheads, I believe up to 7. |
