Recent breakthroughs in ADC biomarkers: Key publications you should know – May, 2025

May 13

RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer.

Summary:
This study identifies RAB5A, a marker of early endosomes, as a predictive biomarker for trastuzumab emtansine (T-DM1) efficacy in HER2-positive breast cancer. Both in vitro analyses and patient data from the I-SPY2 and KAMILLA clinical trials revealed that high RAB5A expression correlates with increased T-DM1 sensitivity. Notably, RAB5A combined with HER2 expression provided a more accurate prediction of T-DM1 response than either biomarker alone.
Why It Matters:
This research underscores the importance of intracellular trafficking components in ADC efficacy. For pharmaceutical development, especially ADCs like T-DM1, biomarkers such as RAB5A could refine patient selection, improve therapeutic outcomes, and guide assay development in clinical trials. CROs engaged in biomarker validation and patient stratification strategies should consider incorporating RAB5A assessment in their service offerings.
Citation:
Engebraaten, O., Yau, C., Berg, K., Borgen, E., Garred, Ø., Berstad, M. E. B., Fremstedal, A. S. V., DeMichele, A., van ’t Veer, L., Esserman, L., & Weyergang, A. (2021). RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer. Nature Communications, 12, 6427. https://doi.org/10.1038/s41467-021-26018-z
Link to original article: https://doi.org/10.1038/s41467-021-26018-z

Summary:
This study compares the intracellular processing of two HER2-targeted antibody-drug conjugates (ADCs): T-DM1 and T-DXd. While T-DM1 efficacy correlates strongly with HER2 and RAB5A expression, T-DXd efficacy is less dependent on HER2 and more loosely associated with RAB5A. Functional studies reveal distinct trafficking pathways, with T-DXd partly relying on RAB4A. The design of the ADC linker critically influences intracellular routing and cytotoxic efficacy.
Why it matters:
This research provides key insights into how intracellular trafficking components affect ADC performance, with implications for biomarker-guided patient selection and ADC design. For pharmaceutical development, especially in oncology, understanding RAB GTPase dependencies can optimize drug design and inform preclinical validation strategies. The findings are directly relevant to ADC biomarker discovery and companion diagnostic development.
Reference:
Medhus, A., Schink, K. O., Longva, A. S., Engebraaten, O., Berg, K., & Weyergang, A. (2025). The mechanisms of HER2-targeted ADCs are dependent on Rab GTPases. Therapeutic Advances in Medical Oncology, 17, 1–17. https://doi.org/10.1177/17588359251332473
Link to original article: https://doi.org/10.1177/17588359251332473

Rab GTPases Drive HER2-Targeted ADC Efficacy: Insights from Comparative Cell Line Analysis

Summary
This study compares two HER2-targeting antibody-drug conjugates (ADCs)—T-DM1 and T-DXd—in HER2-positive breast cancer cell lines. While T-DM1 efficacy correlates with HER2 expression, T-DXd does not. Instead, both ADCs show stronger dependency on the early endosomal regulator RAB5A for cytotoxic efficacy. Knockdown and overexpression experiments confirm the differential trafficking and linker cleavage dependencies of the two ADCs.
Why it matters
The findings highlight the importance of intracellular trafficking, particularly Rab GTPase activity, in determining ADC effectiveness. For pharmaceutical developers, this underscores the need to consider not only antigen expression but also endosomal pathway components like RAB5A in biomarker discovery, ADC design, and patient stratification in clinical trials.
Reference
Medhus, A., Schink, K. O., Longva, A. S., Engebraaten, O., Berg, K., & Weyergang, A. (2025). The mechanisms of HER2-targeted ADCs are dependent on Rab GTPases [Conference presentation]. AACR Annual Meeting 2025.
Link to poster abstract:
View AACR Poster 3307 (search “Weyergang 3307” on the AACR portal)

Utilizing endocytosis as a predictive biomarker for ADCs

Summary
This study presents compelling preclinical and clinical data supporting Rab GTPases—specifically Rab5A and Rabx family members—as predictive biomarkers for the efficacy of antibody-drug conjugates (ADCs) such as T-DM1, T-DXd, and Sacituzumab Govitecan. Rab5A expression correlated with T-DM1 response across three clinical cohorts, while Rabx influenced the cytotoxic effectiveness of T-DXd and SG in breast and lung cancer cell lines. Knockdown experiments confirmed reduced ADC sensitivity when Rab GTPase levels were suppressed.
Why it matters
Identifying reliable biomarkers is critical to precision oncology. These findings emphasize that ADC response is not solely driven by target antigen expression but also by the intracellular trafficking capacity governed by Rab GTPases. For pharma and biotech developers, incorporating Rab GTPase profiling could enhance patient selection, optimize ADC design, and refine clinical trial stratification strategies.
Link to poster abstract
View AACR Poster 3104 (search “Medhus 3104” on the AACR portal)

Hans Christian Pedersen