me-better for DS8201 has appeared

DS8201 also has defects, mainly the side effects of interstitial pneumonia, which led to nearly 20% treatment interruption. Some clinicians and I reported that when 8201 was applied in China, many patients could not bear the side effects, leading to reduction or treatment interruption.

So is interstitial pneumonia an in-target side effect or an out-target side effect?

If it is an intra target side effect, why does TDM1 and HER2-ADC with multiple MMAE and MMAF not have this side effect at all?

Therefore, the probability of interstitial pneumonia is not the target side effect, but the probability of toxin shedding side effect is greater, and may be related to the toxin DXd, because other toxins also shed, and there is no such side effect.

Other studies suggest that Fc function of HER2 antibody causes interstitial pneumonia, but ADC with complete Fc function, such as TDM1, does not have this side effect.

However, sutro changed linker into glucuronidase digestion linker in preclinical studies, and found no interstitial pneumonia, which needs to be confirmed by clinical trials.

The DAR of 8201 is 8, with mercapto coupling, which is easy to fall off in the reverse Michael reaction. The DXd property and the probability of falling off leading to interstitial pneumonia is relatively high. Site-site coupling can be used to reduce the fall off.

The previous two double-antibody ADCs were clinically unsuccessful. The common problem was that there was no bystander effect, and the toxin toxicity was too high, and it was easy to shed.

The hepatotoxicity of MEDI4276 may be caused by the toxin ablating and aggregation in the liver, the MMAE payload of ZW49, the toxicity is still too large, the conjugation is also unstable, the double antibody itself is also unstable, the half-life is short, resulting in poor dose, poor effect, and its patent shows that two monkeys died in the preclinical high DAR.

In other words, the previous failure of the two-site ADC is probably not the problem of the two-site, but the toxin and coupling are inappropriate.

In general, site-specific coupling can reduce toxin shedding and improve internalization efficiency with dual sites, which are the improvement directions of 8201.

As for the effect, we will see.