Raffaele Colombo
@raffcolo
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ADCs, targeted therapies, chemistry, biotech, pharma. Associate Director @ Zymeworks
Vancouver, British Columbia
Joined October 2022
🎉 It's an incredible honor and privilege to be named one of the 2024 PharmaVoice 100 by @PharmaVoice, alongside so many talented and inspiring leaders in the life sciences industry! 🎉. Check out the full list of this year #PharmaVoice100 honorees here:
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. also true for many presentations at conferences!.
How NOT to give grand rounds. A smart, tongue-in-cheek guideline from David Johnson in @JCOOP_ASCO . An Oncologist's Guide to Ensuring Your First Medical Grand Rounds Will Be Your Last | JCO Oncology Practice
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Blazing-fast image creation – using just your voice. Try Grok Imagine.
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For whatever reason, some figures have poor quality. Higher resolution 👇
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While ILD appears to be related to linker-payload in some cases, the proposed mechanism involving methylamine, amine oxidase, and H2O2 from hemiaminal linkers is wrong!. And formaldehyde generated from ADCs is released over time at levels far below endogenous concentrations!
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The release from ADC occurs over several days and not all in the lung! . Importantly, ILD observed with ADCs is not strictly related to hemiaminal motif: some ADCs with non-hemiaminal linkers have shown ILD and some ADCs with hemiaminal linkers have shown minimal ILD.
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89Zr-trastuzumab lung uptake was low (significant, but still low), meaning the amount of formaldehyde released in the lung is even less than the total 0.0086 mg/kg potentially generated from the ADC. Slide from @VriesElisabeth #AACR25 @AACR
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This is even less than the estimated daily intake of formaldehyde from food, which ranges from 1.4 to 1.7 mg/kg body weight per day for a 60-70 kg person.
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A 5.4 mg/kg dose of T-DXd (Q3W), bearing 8 copies of the linker (DAR = 8), corresponds to formation of at most 0.0086 mg/kg of formaldehyde (Q3W) coming from the ADC…. ….which is far less (<1/100,000) than of the body’s daily formaldehyde turnover!. 🤯🤯.
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Blood and intracellular steady state concentrations of formaldehyde have been estimated to be around 3 mg/L (100 μM) and 12 mg/L (400 μM) in humans, respectively. Formaldehyde half-life in humans is very short (estimated to be 1-1.5 min).
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Daily endogenous turnover of formaldehyde has been estimated to be ~0.6-0.9 mg/kg per minute (~900-1300 mg/kg per day).
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The formation of formaldehyde as metabolite is possible, but it lacks biological relevance. Our bodies continuously produce formaldehyde through biological processes, and we also intake formaldehyde from food.
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Finally, they speculate that hydrogen peroxide and formaldehyde can cause inflammation and crosslinking. While no hydrogen peroxide is actually formed, formaldehyde is indeed a metabolite and so warrants further discussion.
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Sloot et al. further propose the involvement of an enzyme, amine oxidase, to convert methylamine into ammonia, formaldehyde, and hydrogen peroxide. This is flawed, as methylamine is not formed at any stage in the cleavage pathway of this linker.
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Daiichi reported that for T-DXd metabolism: “an amino-methylene (AM), which is designed as a self-immolative spacer, is rapidly hydrolyzed to ammonia and formaldehyde”. Amino-methylene is not methylamine!.
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The authors claim that ADCs with hemiaminal linkers, like T-DXd, yield methylamine (MA) after cleavage by proteases. This is simply wrong. Can’t break chemical bonds like that!
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First, the link to the original paper: And the recent publication of M9140 phase 1 data, which amplified this putative ILD mechanism:
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Sloot et al. published a paper proposing a putative mechanism for ILD, suggesting the involvement of a specific component of the DXd linker (the hemiaminal). While an understanding of how ADCs can cause ILD is lacking, their explanation has several issues!. A thread 🧵👇
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