The mechanisms of HER2 targeted ADCs are dependent on Rab GTPases

What if the key to ADC efficacy lies not in the target, but in the cell’s trafficking machinery?
In recent publication by Medhus co-authored by founders of Rab Diagnostics Anette Weyergang, Olav Engebraaten and Kristian Berg, the study shows that the mechanisms of HER2-targeted ADCs T-DM1 and T-DXd depend heavily on Rab GTPase-regulated trafficking, not just HER2 expression.

Key Findings:

• T-DM1 efficacy strongly correlates with HER2 + RAB5A expression.

• T-DXd efficacy depends primarily on RAB5A, independent of HER2 levels.

• Linker design dictates whether payload release requires full lysosomal trafficking (T-DM1) or occurs earlier (T-DXd).

• Bystander killing is crucial for T-DXd effectiveness in HER2-low settings.

  Impact:
  ✅ Intracellular trafficking pathways should be studied during development of ADCs
  ✅ RAB5A emerges as a predictive biomarker for the efficacy of two different HER2-targeted ADCs.
  ✅ Tailoring ADC design to trafficking mechanism could enhance clinical outcomes.
  
  Read the article here:
  https://journals.sagepub.com/doi/epub/10.1177/17588359251332473