That’s a wrap for the day on antibody drug conjugates at the @mitkochinstitute.bsky.social ! Awesome course on these complicated and exciting molecules (and their relatives)! Lots more exciting anti-cancer science to come 💊 #KIsymposium

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

Michael Seganish closes out the day discussing what happens when an ADC payloads detaches, even when it’s supposed to, and gets into circulation instead of into its target cell. Spoiler alert: toxic side effects @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

Puja Sapra brings perspective on the evolution of the ADC field: much learned and much to be done in terms of improving targets, understanding why different ADCs work differently, and deriving novel combos for future use. @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?

Greg Thurber starts session 3 with perspective on the trajectory of ADCs in the clinic & in research- there's been a steady increase in approved ADC molecules for clinical use since early 2000s! @mitkochinstitute.bsky.social #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. @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

Daša Lipovšek expanding today's discussion to include miniprotein radioconjugates, which link target-binding proteins with radioisotopes that can kill cells or be detected with imaging devices. This facilitates greater targeting and functionality. @mitkochinstitute.bsky.social #KIsymposium

Jeremiah Johnson's antibody-bottlebrush conjugates aim to enable loading more drug onto ADCs using hydrophilic sidechain linkers that stabilize more, larger, & combos of payloads. This opens doors to more options for ADC design across more contexts @mitkochinstitute.bsky.social #KIsymposium

Dane Wittrup's lab is innovating ADCs by designing linker-less ADCs, which can enable release of payloads that cells can then take up over time- enabling better and potentially more potent targeting @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

Kicking off session 2 is Laurie Boyer, discussing how to visualize how molecules (like ADCs) are traveling into and around cells. Regular light microscopy isn't sufficient and more complicated super-resolution microscopes are expensive and hard to use.

Last in Session 1: Timothy Lowinger discusses targeting immune pathways! STING agonism activates innate immunity, but it's important and difficult to deliver this only to tumor lesions. ADCs can bring the drug directly to the tumor microenvironment @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

Alison Betts: With the promise of ADCs comes a need to better understand their mechanisms + toxicities. Quantitative Systems Pharmacology modeling uses applied math to study data from ADC trials, aiding in the design of new & improved versions. @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

Next in session 1: Gerold Meinhardt with clinical data on Trastuzumab Deruxtecan, a HER2 ADC with great efficacy for breast cancer patients in a variety of contexts, including patients that have already been treated with other agents @mitkochinstitute.bsky.social #KIsymposium

Lots of opportunities to use ADCs in the clinic: changing linkers, using different payloads, & modifying targets can open doors for a variety of diseases and contexts- sometimes through unexpected mechanisms that can be understood and studied further! @mitkochinstitute.bsky.social #KIsymposium

One challenge: antibodies usually sit on the cell surface- this can be OK! But, how to get more effectively drugs into the cells? Bispecifics can help- two targets can be better than one. Or, non-antibodies that bind receptors (for example) can also deliver drugs. @mitkochinstitute.bsky.social

Now, Peter Senter discussing challenges and progress in antibody drug conjugates for cancer- tricky in terms of design, potency, toxicity, etc. However, ADCs have already led to huge improvements, such as in Hodgkin's lyphoma and urothelial cancer. #KIsymposium @mitkochinstitute.bsky.social

2)"Click to release"- delivering chemotherapy (as an example) that is 'caged' in a protodrug that only activates (using click chemistry) to a specific location in the body (lowering side effects, increasing specificity, etc) @mitkochinstitute.bsky.social #KIsymposium