The Revolution of Antibody-Drug Conjugates in Cancer Treatment

The Dawn of the Antibody–Drug Conjugates Era: How T-DM1 Reinvented the Future of Chemotherapy for Solid Tumors

Developing effective cancer treatments with fewer side effects remains a paramount goal in oncology. Paolo Tarantino and Sara M. Tolaney dive deep into a groundbreaking development that has reshaped the future of chemotherapy for solid tumors.



The Rise of T-DM1: A Game Changer

In 2013, trastuzumab emtansine (T-DM1) became the first ADC approved for treating solid tumors, specifically HER2-positive metastatic breast cancer. Its origin traces back to the influential 2008 Cancer Research publication by Lewis Phillips and team. This research showcased T-DM1’s efficacy, improved stability, and reduced toxicity, particularly when combined with a specific thioether linker.


Transformative Findings and Implications

Several pivotal observations arose from this research:
1. T-DM1 demonstrated heightened potency against HER2-positive cells compared to trastuzumab alone.
2. Different linkers used in creating ADCs significantly impacted pharmacokinetics. Notably, a thioether linker showcased the highest stability, improving T-DM1’s anticancer activity.
3. Enhanced linker stability reduced toxic side effects. As a result, T-DM1 presented a more favorable toxicity profile than other treatments.
The profound implications of these findings were quickly realized in clinical settings, with T-DM1 showing improved survival rates for metastatic HER2-positive breast cancer patients.


Expanding the Horizon: Future of ADCs in Oncology

The success of T-DM1 sparked interest in developing other ADCs targeting varied antigens. For example, trastuzumab deruxtecan (T-DXd) emerged as another ADC, demonstrating transformative activity across various cancers, including breast, gastric, and lung cancers. Although these new ADCs deliver more potent treatment, they sometimes come at the cost of increased toxicity. Nevertheless, ongoing clinical trials for early-stage tumors hint at the possibility of eradicating cancers before they metastasize.
Fourteen years post the revolutionary publication by Phillips and colleagues, ADCs have taken center stage in oncology. This shift suggests a gradual move from traditional chemotherapy to a more targeted delivery method. The future holds even more promise, with advancements like bispecific mAbs and novel conjugating strategies on the horizon.


In conclusion, while the “magic bullet” for cancer treatment may not be a single solution, the combined power of ADCs offers a brighter, more tailored future in oncology.


Tarantino P, Tolaney SM. The Dawn of the Antibody-Drug Conjugates Era: How T-DM1 Reinvented the Future of Chemotherapy for Solid Tumors. Cancer Res. 2022 Oct 17;82(20):3659-3661. doi: 10.1158/0008-5472.CAN-22-2324. PMID: 36245247.