In Column A, we focus on Enhertu, the ADC that appears repeatedly throughout this series, and ask a simple but far-reaching question:
Why did this particular ADC become such a central reference point in the current ADC land grab?
We will look at Enhertu through three lenses:
- Design – what makes this ADC structurally distinctive?
- Clinical development – what was unprecedented or unusual about its indication and line expansions?
- Business strategy – how did it influence deals, portfolios, and platform thinking across the industry?
The aim is not to retell every detail of its development history, but to extract practical lessons for people who are now developing, investing in, or evaluating ADCs.
1. Design Perspective: What Makes the “Enhertu-type” ADC Different?
1.1 Antibody × High DAR × Topoisomerase I Inhibitor Payload
Enhertu is an ADC targeting HER2, with a topoisomerase I inhibitor payload and a relatively high drug-to-antibody ratio (DAR). Key design features, in simplified form, include:
- high DAR – many payload molecules per antibody,
- a linker designed to be stable in circulation yet cleavable in the tumor environment,
- a membrane-permeable payload that enables a bystander effect.
Together, these elements support cytotoxic effects not only in strongly HER2-expressing cells but also in neighboring cells with lower HER2 expression. This feature became central to how Enhertu was used and perceived.
1.2 Challenging the Old “HER2-positive Only” Paradigm
A second, equally important point is that Enhertu demonstrated benefit in patient groups that had not historically been treated as “HER2-positive”. This led to:
- a re-examination of what “HER2-positive” should mean in practice,
- a new challenge: how to define and select “HER2-low” populations in a robust, clinically actionable way.
In short, Enhertu helped push the field toward treating ADC design and biomarker strategy as a single integrated problem, rather than separate checkboxes.
2. Clinical Perspective: Indication Expansion and the Impact of “HER2-low”
2.1 Speed and Breadth of Indication Expansion
One reason Enhertu attracted so much attention was the speed and breadth of its indication and line extensions. Without dwelling on specific timelines or trial names here, the key themes are:
- initial approvals in defined breast cancer subgroups, followed by substantial expansion of the treatable population,
- the emergence of “HER2-low” as a clinically relevant category with real therapeutic options.
For clinicians and companies alike, this altered the perceived size and structure of the ADC opportunity.
2.2 Biomarker Practice and Real-world Gaps
At the same time, the “HER2-low” concept highlighted several practical challenges:
- reproducibility of pathology assessments across sites and pathologists,
- inter-institutional variability in diagnostic standards and workflows,
- the gap between the theoretical eligible population and the number of patients actually treated in real-world practice.
Enhertu’s experience underscores a broader point: ADC opportunity size is constrained not only by biology and regulation, but also by diagnostic practice and healthcare infrastructure.
2.3 Safety Profile and Risk Management
Like many potent ADCs, Enhertu is associated with distinct safety considerations. From a learning perspective, important elements include:
- awareness of class-specific adverse events affecting particular organs,
- clear rules for treatment continuation, dose modification, and discontinuation,
- balancing risk and benefit in patient selection and monitoring.
A key takeaway here is that greater efficacy raises, rather than lowers, the bar for safety evaluation and risk management.
3. Business Perspective: Demonstrating the Value of an ADC Platform
3.1 From Single Product to Platform Value
Enhertu’s success did more than validate a single drug; it showcased the business value of an ADC platform. Among the lessons:
- the potential to extend the same technology backbone to new targets and indications,
- the feasibility and value of co-development and co-promotion structures across regions,
- the impact of a strong ADC franchise on overall corporate valuation and strategic positioning.
For other companies, this has become a reference point when deciding whether—and how—to invest in in-house ADC platforms.
3.2 A Reference for Deal Structures
Partly because of its visibility, Enhertu has also functioned as a reference case for ADC deal making:
- headline deal sizes, upfront payments, and royalty structures,
- division of territorial rights and commercialization responsibilities,
- allocation of development risk and investment burden.
Not every deal can or should resemble this template, but the existence of a high-profile success story inevitably shapes expectations and negotiation baselines across the market.
3.3 Psychological Acceleration of the ADC Land Grab
Beyond hard numbers, the psychological impact of Enhertu should not be underestimated:
- no one wants to “miss the next Enhertu,”
- few organizations want to appear late or absent from the ADC wave,
- investors and corporates alike feel pressure to have at least some ADC exposure.
Together, these factors have contributed to the intensity and sometimes overheated tone of the current ADC land grab. Enhertu is not the sole cause, but it is certainly one of the strongest catalysts.
4. Lessons from Enhertu: Where Science, Clinics, and Business Intersect
4.1 Science: Integrating Target, Design, and Biomarkers
From a scientific standpoint, Enhertu illustrates the importance of integrating:
- target selection – even “old” targets can open new markets when viewed through a different design lens,
- ADC design – payload, DAR, and linker choices can implement new therapeutic concepts such as robust bystander effects,
- biomarker strategy – moving beyond binary positive/negative classifications where biology supports it.
ADC programs that treat these three dimensions as independent often struggle to reach their full potential.
4.2 Clinical: Designing for Expansion and Real-world Adoption
Clinically, Enhertu’s trajectory highlights the value of
- thinking beyond the first approval toward future indication and line extensions,
- choosing endpoints and trial designs that clearly differentiate the product,
- anticipating real-world implementation—diagnostics, reimbursement, treatment algorithms—from early in development.
The path from first label to broad real-world impact is rarely linear; building that path into development strategy can be decisive.
4.3 Business: Platform Thinking and Thoughtful Risk-sharing
From a business perspective, key themes include:
- creating value at the platform level, not just at the single-asset level,
- using co-development and co-promotion to design balanced risk-sharing structures,
- crafting partnership strategies that work across both global and regional dimensions.
High-risk, high-cost modalities like ADCs rarely succeed in isolation; carefully designed collaborations often play a central role.
My Reflections
Enhertu is more than a highly active ADC. It represents a shift in how the field thinks about targets, bystander effects, indication expansion, and platform economics. In that sense, it has “moved the clock forward” for ADCs as a whole and has legitimately contributed to the intensity of today’s ADC land grab. At the same time, it is crucial to remember that Enhertu’s trajectory is not a simple template that can be replicated at will. The same design ideas will play out very differently when the target biology, patient populations, competitive landscape, safety profile, and manufacturing capacity all change.
For those developing, investing in, or assessing ADCs today, the most useful approach may be to treat Enhertu not as a blueprint, but as a source of principles. Integrating target biology, ADC design, biomarker strategy, and business model from the outset; anticipating how trial results will translate into real-world practice; and being thoughtful about platform-level value and risk-sharing—these are the types of lessons that can travel across programs and companies. In that sense, the lasting impact of Enhertu may lie less in the specific molecule and more in how it has raised the ambitions—and the expectations—around what an ADC program can and should be.
This article has been edited by the Morningglorysciences team.
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