Antibody–drug conjugates or ADCs selectively deliver a a cytotoxic payload to target cancer cells, making them important anti-cancer therapeutics.

The specificity of ADCs and the local release of the cytotoxic payload are the main parameters that provide increased anti-cancer efficacy decreaseing systemic toxicity. As a result, ADCs have, a wider therapeutic window compared to traditional chemotherapeutic agent.

But the mechanisms by which antibody-drug conjugates are internalized and activated have, so far, remained unclear.

Using CRISPR-Cas9 screens (Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR Associated Nuclease 9), Kimberly Tsui, Robyn Barfield, Curt Fischer, et al, uncover many known and novel endolysosomal regulators as modulators of ADC toxicity.

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The scientists identified and characterized C18ORF8/RMC1, as a member of the CCZ1-MON1 GEF complex, as a regulator of ADC toxicity through its role in endosomal maturation. Further, through comparative analysis of screens with ADCs bearing different linkers, they demonstrated that a subset of late endolysosomal regulators selectively influence toxicity of noncleavable linker ADCs.

Surprisingly, the researchers noted that cleavable valine–citrulline linkers can be processed rapidly after internalization without lysosomal delivery. Finally, Tsui, Barfield, Fischer, et al, demonstrated that depletion of sialic acid (N‐acetylneuraminic acid) enhances ADC lysosomal delivery and killing in diverse cancer cell types. The scientists observed this in trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells.

The results of the study reveal new regulators of endolysosomal trafficking. This provides important insights for the design of novel antibody-drug aonjugates and identifies candidate combination therapy targets.

Tsui CK, Barfield RM, Fischer CR, Morgens DW, Li A, Smith BAH, Gray MA, Bertozzi CR, Rabuka D, Bassik MC. CRISPR-Cas9 screens identify regulators of antibody-drug conjugate toxicity. Nat Chem Biol. 2019 Aug 26. doi: 10.1038/s41589-019-0342-2. [Pubmed][Article]

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