Ian Wilkinson: What the Fc is up with ADCs?
Ian Wilkinson, Chief Executive Officer at
“What the Fc is up with ADCs?
ADCs are the hot topic in antibodies at the moment. Not a week goes by that we don’t see news of another ADC entering the clinic or being acquired. Much of the appeal of ADCs is their phenomenal potency but this is a double edged sword and toxicity is a real risk.
It’s always struck me as odd that ADC developers don’t seem to pay much attention to the Fc domain. Surely for most ADCs effector function (i.e. ADCC, ADCP or CDC) isn’t part of the primary mechanism of action? If that’s the case then the logical approach would be to utilise an Fc domain with reduced effector function to avoid unwanted toxicity from binding to and killing immune cells expressing Fc gamma receptors. ADCs are toxic enough as it is so why run this risk?
I always had the feeling this was largely ignored in the ADC space but didn’t have the stats to back this up. So yesterday I looked at 70 ADCs, which was most if not all the ADCs that had been in the clinic up to 2022. Over 90% had a fully active human IgG1 Fc domain. This is in stark contrast to antibodies as a whole (from an analysis of +800 INNs) where about 45% are ‘silenced’./article/
As a developer of one of the best silencing mutations I’m somewhat biased, but what’s going on here? Are ADC developers missing a trick or is there some logic to the choice of wild type IgG1 in almost all cases? I’d love to hear from people developing ADCs!/article/
Note – my analysis doesn’t account for the fact that some of these antibodies will utilise the glycans for site-specific conjugation of the payload and this will presumably reduce effector function to some extent. I don’t have details on the conjugation process for each mAb in my dataset but I expect that glycan conjugated mAbs only account for a small number (although I accept this is becoming increasingly common in recent years).”
Source: Ian Wilkinson/LinkedIn