ADC Series (II): ADC Evolution: Why Today’s Antibody–Drug Conjugates Are Different
- Jason Lu
- 1 day ago
- 4 min read
This is the second article in LuTra Studio’s ADC series, written for readers without prior ADC expertise who want to understand ADC evolution—specifically, why antibody–drug conjugates experienced widespread failures in the 2000s but emerged as one of the most important oncology platforms after 2020.
Rather than starting with definitions, this article traces the historical failures, engineering corrections, and strategic shifts that shaped modern ADC development across different ADC generations.
Executive Summary | One Key Takeaway
If you remember only one thing:
ADCs did not suddenly become successful — they spent more than a decade learning which designs were destined to fail.
What appears today as a technological breakthrough is, in reality, the result of accumulated engineering discipline, biological insight, and platform-level thinking.
1. The Starting Point: Why Early ADC Development Failed So Often
(Early ADC Development Challenges)
Between 2000 and 2010, ADCs were widely viewed as an intuitively powerful idea:
Use antibodies to deliver highly potent drugs directly into cancer cells.
In clinical reality, however, many early ADC programs failed due to:
Inconsistent or insufficient efficacy
High molecular heterogeneity and poor manufacturability
These failures did not invalidate the ADC concept itself. Instead, they revealed how overly optimistic early assumptions about in vivo behavior led to predictable failure modes.
2. First-Generation ADCs: The Problem Was Not Potency, but Loss of Control
(First-generation ADCs)
First-generation ADCs shared several defining characteristics:
Unstable linkers that released payloads prematurely in circulation
Random conjugation, leading to broad and uncontrolled DAR distributions
Highly potent payloads without sufficient spatial or temporal control
The result was clear:
Many ADCs caused toxicity before ever reaching their target cancer cells.
Early examples such as Mylotarg taught the industry a critical lesson:
The problem was not that the drugs were too toxic — the problem was that they were released at the wrong time and in the wrong place.
3. Second-Generation ADCs: Learning Control, with Remaining Limitations
(Second-generation ADCs)
Second-generation ADC development introduced meaningful improvements:
Humanized antibodies with reduced immunogenicity
More stable cleavable or non-cleavable linker designs
Better-characterized payloads such as MMAE and DM1
These advances demonstrated, for the first time, that:
With sufficient control, ADCs can succeed clinically.
Approved drugs such as Adcetris and T-DM1 validated the ADC approach.
However, limitations remained:
Modest efficacy in many solid tumors
Emerging resistance mechanisms
Designs optimized for single products rather than platforms
4. The Inflection Point: Why Third-Generation and Next-Generation ADCs Are Different
(Next-generation ADCs)
Post-2020 ADC success is not driven by greater toxicity, but by greater system-level intelligence.
4.1 Payload Transformation
The introduction of topoisomerase I inhibitors and other next-generation payloads enabled consistent efficacy in solid tumors and introduced meaningful bystander effects.
4.2 Engineering Discipline
Site-specific conjugation
Predictable DAR distributions
Improved molecular homogeneity and pharmacokinetics
ADCs began to resemble engineered products rather than trial-and-error constructs.
4.3 Platform-Oriented Design
Modern ADCs are designed with future extensibility in mind:
Can the same architecture support multiple targets?
Can payloads or linkers be swapped systematically?
This shift marked the true beginning of ADCs as scalable therapeutic platforms.
5. How ADC Evolution Reshaped Drug Development and Industry Strategy
As ADC risk profiles changed, industry behavior followed:
Increased M&A activity targeting ADC-focused companies
Rapid growth in licensing deal valuations
ADCs repositioned as long-term platform investments rather than isolated assets
ADC evolution transformed ADCs from high-risk experiments into repeatable innovation engines.
6. What ADC Evolution Means for Teams Developing ADCs Today
For teams entering ADC development today, there is both good news and bad news:
Good news: You no longer need to repeat early-generation failures
Bad news: The bar for success is significantly higher
Modern ADC failures often stem not from outdated technology, but from:
Product-level thinking rather than platform-level design
Failure to integrate internalization, linker chemistry, and payload biology as a unified system
Learning from ADC Evolution | LuTra Studio Consulting
The history of ADC evolution is, fundamentally, a story of learning systems thinking through failure.
At LuTra Studio, we help teams translate these hard-earned industry lessons into early-stage decision frameworks, addressing questions such as:
Which ADC generation does your design truly resemble?
Are you building a single asset or a scalable platform?
Which early design decisions may become structural liabilities later?
If you prefer not to pay for these lessons through late-stage clinical failure, we welcome further discussion.
What’s Next | ADC Series (III)
The next article in this series will focus on:
Linkers and Conjugation: The True Engineering Core of ADCs — and Why It Is So Often Underestimated
Follow LuTra Studio for continued deep dives into next-generation drug platforms.
References
Beck, A., Goetsch, L., Dumontet, C., & Corvaïa, N.
Antibody–Drug Conjugates: Present and Future.
Nature Reviews Drug Discovery, 2017.
Lambert, J. M., & Morris, C. Q.
Antibody–Drug Conjugates (ADCs) for Targeted Cancer Therapy.
Advanced Therapy (Adv Ther), 2017.
Drago, J. Z., Modi, S., & Chandarlapaty, S.
Unlocking the Potential of Antibody–Drug Conjugates for Cancer Therapy.
Nature Reviews Clinical Oncology, 2021.
Sievers, E. L., & Senter, P. D.
Antibody–Drug Conjugates in Cancer Therapy.
Annual Review of Medicine, 2013.
https://www.annualreviews.org/doi/10.1146/annurev-med-050913-022434
U.S. Food and Drug Administration (FDA).
Drug Approval Package: Mylotarg (gemtuzumab ozogamicin).
2000.
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21047_Mylotarg.cfm
Ogitani, Y., et al.
DS-8201a, a Novel HER2-Targeting Antibody–Drug Conjugate, Demonstrates a Promising Antitumor Efficacy.
Clinical Cancer Research, 2016.
https://aacrjournals.org/clincancerres/article/22/20/5097/247874
Journal of Hematology & Oncology (Springer / BioMed Central).
Antibody–Drug Conjugates: Current and Future Biopharmaceuticals.
Journal of Hematology & Oncology, 2025.
https://link.springer.com/article/10.1186/s13045-025-01704-3
ADC Review / Journal of Antibody–Drug Conjugates.
Engineering the Future of Cancer Care: How Next-Generation Antibody–Drug Conjugates Are Shaping Oncology and Beyond.
Novotech CRO.
Comprehensive Report: Antibody–Drug Conjugates Clinical Trials Landscape 2024.