Modifying chemistry of ADCs, such as through adding polar groups to increase lipophilicity is a separate approach that helps improve ADC pharmacokinetics and tolerability @mitkochinstitute.bsky.social #KIsymposium

Different toxicities can appear with better linkers- indicating a need to better understand the biology of ADCs, as well as improve in other ways to mitigate this toxicity @mitkochinstitute.bsky.social #KIsymposium

With an unstable linker, side effects mimic those of non-ab mediated systemic treatment with the same drug and safe dosage levels are no different. Stable linkers improve this, safely enabling higher payload doses. TLDR; linker is critical! @mitkochinstitute.bsky.social #KIsymposium

A new challenge: what to do after development of resistance to ADC treatment- re-treating with a new ADC often doesn’t work. More to learn! #KIsymposium @mitkochinstitute.bsky.social

What biomarkers predict success on ADCs? 2 AI models work together to automate image analysis and identify tumor cells that are targetable by ADCs, defining a signature that can be used to identify strong patient candidates. @mitkochinstitute.bsky.social #KIsymposium

More quantitative systems modeling in the Thurber lab has helped identify these balances given lots of data- aiding in figure design of these molecules, which don’t follow the same principles as other drugs. #KIsymposium

One approach: lower drug to antibody ratio gets drug into the tissue more efficiently and improves efficacy overall while lowering concerns about toxicity. Second: Use more of a lower potency payload that's more tolerable- It's all about balance. #KIsymposium

Mouse models have taught lessons about how ADCs biodistribute + enter tissue which isn't always well- a challenge to be overcome. Higher/more frequent dosages don't always fix this, since there's a risk of toxicity with higher payload. #KIsymposium

Challenges remain: most ADCs don't reach the tumor and still circulate (though don't bind), and what does often doesn't distribute through the tumor well. How do we think about fixing?

Mouse models have taught lessons about how ADCs biodistribute + enter tissue which isn't always well- a challenge to be overcome. Higher/more frequent dosages don't always fix this, since there's a risk of toxicity with higher payload. @mitkochinstitute.bsky.social #KIsymposium

Challenges remain: most ADCs don't reach the tumor and still circulate (though don't bind), and what does often doesn't distribute through the tumor well. How do we think about fixing? @mitkochinstitute.bsky.social #KIsymposium

With a smaller size and shorter half-life in the body than ADCs, they can get into tumors better, clear out of normal tissues more easily, while still being potent and specific @mitkochinstitute.bsky.social #KIsymposium

The Boyer lab optimized physically expanding cells and then imaging them in a 96-well plate format- reaching the resolution of higher-power instruments without the cost. Now ADCs at work can be observed! @mitkochinstitute.bsky.social #KIsymposium

So much can be done with these models combining in vitro, mouse, and clinical studies- understanding bystander effects of ADCs, studying off-target toxicities, and even creating computer-simulated trials to predict what would happen in patient cohorts. @mitkochinstitute.bsky.social #KIsymposium

It makes sense that this therapy might work in HER2+ patients. But a big question today- why do these also show efficacy in HER2-low (even ultra-low!) patients? Exciting results and lots to learn still... @mitkochinstitute.bsky.social #KIsymposium