Over the past few years, the landscape of Antibody-Drug Conjugates (ADCs) has undergone a dramatic transformation, shifting from a niche therapeutic approach to a central pillar of oncology innovation. This bonus chapter highlights recent breakthroughs, the intensifying global race in ADC development, and offers a preview of what’s next in our series: in vivo CAR-T cell therapies.
Enhertu: A Paradigm-Shifting Breakthrough
Perhaps no other ADC exemplifies the potential of this therapeutic class more than Enhertu (trastuzumab deruxtecan), co-developed by Daiichi Sankyo and AstraZeneca. Originally designed to target HER2-positive breast cancer, Enhertu surprised the oncology world by demonstrating striking efficacy even in patients with low HER2 expression—ushering in the concept of “HER2-low” as a new therapeutic category.
Enhertu’s success lies in its optimized design: a high drug-to-antibody ratio (DAR ~8), a cleavable linker that is stable in circulation but efficiently cleaved within tumor cells, and a potent topoisomerase I inhibitor payload. Moreover, its bystander effect enables payload diffusion into neighboring cells regardless of HER2 expression, contributing to broader antitumor activity.
FDA approvals have expanded from HER2-positive metastatic breast cancer to HER2-low and HER2-mutant lung and gastric cancers, rapidly making Enhertu one of the most valuable oncology assets in the global pharmaceutical pipeline. Its blockbuster status has sparked renewed interest in ADC platforms and encouraged big pharma to aggressively enter the field.
The Global ADC Arms Race: Who’s Leading?
Following Enhertu’s rise, the ADC space has become fiercely competitive. Over 100 ADCs are now in clinical development, targeting diverse antigens with novel linker-payload combinations. Here’s a snapshot of recent movements:
- Seagen (acquired by Pfizer) continues to dominate with Adcetris and Padcev, and is expanding into solid tumors.
- ImmunoGen’s Elahere, approved for FRα-positive ovarian cancer, marked another validation for the ADC approach.
- Merck, Gilead, and Sanofi are investing heavily in ADC pipelines via partnerships and acquisitions.
- In China, RemeGen and Bio-Thera are developing high-quality ADCs that are now entering global trials.
Technological innovations are also advancing. Novel payloads such as immune-stimulating agents, DNA alkylators, and even dual payload strategies are being tested. Site-specific conjugation methods, new linker chemistries, and AI-driven design tools are enhancing safety profiles and tumor selectivity.
The Future: Beyond Traditional ADCs
Next-generation ADCs aim to solve key challenges—minimizing off-target toxicity, overcoming resistance, and expanding indications. Dual-antigen targeting ADCs and immune-modulatory payloads are at the frontier. ADCs are also being explored for non-oncology indications, including autoimmune diseases and infectious diseases.
In parallel, companies are developing ADC-like formats such as radioimmunoconjugates, bispecific ADCs, and ADC-prodrug hybrids, blurring the line between modalities and offering new treatment paradigms.
Next Up: A New Frontier—In Vivo CAR-T
As ADCs continue their evolution, another revolution is quietly gaining momentum: in vivo CAR-T cell therapy. Instead of extracting and engineering T cells ex vivo, this novel approach enables the body to generate CAR-T cells internally via targeted gene delivery. It promises to overcome key limitations in manufacturing, cost, and scalability.
In our next series, we’ll delve into this exciting technology—its science, startups driving the field, and its implications for the future of immunotherapy.
Stay tuned for: “In Vivo CAR-T Series: Introduction to the Next Generation of Cell Therapy.”
MorningGlorySciences is provided a series of life science and therapeutics news.
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