In Part 1 of this series, we explored why the ADC land grab is happening now and how ADCs fit into the broader oncology landscape.
In Part 2, we reviewed ADC design—antibody, payload, linker, conjugation—and discussed what people mean by first-, second-, and “third-generation” ADCs.
In Part 3, we connected patent cliffs to the ADC rush and framed ADCs as part of long-term big pharma portfolio strategies.
In Part 4, we looked at the structures of ADC transactions—M&A, licensing, co-development, and CDMO agreements—and offered practical ways to read those deals.
In Part 5, we examined the rise of Chinese and other Asian ADC players, their impact on global deal structures, and possible roles for Japan.
In this sixth part, we turn to the relationship between ADCs and other modalities and ask a central question: How can we design oncology portfolios that do not over-rely on ADCs alone?
We will address:
- Where ADCs are strongest, and where their limitations become apparent,
- how ADCs relate to bispecific antibodies, cell therapies, and radiopharmaceuticals,
- how to position ADCs within treatment sequences and life-cycle strategies,
- how investors and consultants can evaluate a company’s overall modality mix.
ADCs Are Powerful, but Not Omnipotent
Strengths: Targeting, Intracellular Delivery, and Potent Cytotoxicity
To start, it is worth restating what ADCs are good at:
- targeting via antibodies that preferentially bind tumor-associated antigens,
- intracellular delivery of payloads through receptor-mediated internalization and release,
- high cytotoxic potency that can overcome resistance to conventional agents,
- compatibility with diagnostic biomarkers such as IHC for target expression.
These features make ADCs attractive for heavily pretreated patients and for tumors where conventional antibodies or small molecules have underperformed.
Limitations: Safety, Resistance, Cost, and Complexity
At the same time, ADCs have clear limitations:
- safety issues including off-tumor toxicity and class-specific adverse events,
- resistance driven by antigen loss, efflux pumps, or DNA repair mechanisms,
- cost of development, manufacturing, and ultimately therapy itself,
- complex manufacturing and supply chains that span biologics and small-molecule chemistry.
For these reasons, a portfolio that leans too heavily on ADCs is structurally fragile. The question is not whether ADCs are valuable—they clearly are—but how they should share the stage with other modalities.
Key Complementary and Competing Modalities
Bispecific Antibodies
Bispecific antibodies, especially T-cell–engaging bispecifics (e.g., CD3×tumor antigen), offer direct immune activation against tumor cells.
- Advantages: potent cytotoxicity via T-cell recruitment; often suitable for fixed-dose regimens.
- Challenges: cytokine release syndrome, need for careful step-up dosing and monitoring.
Relative to ADCs, key questions include:
- for a given target, is it more rational to deploy an ADC or a T-cell–engaging bispecific?
- how do disease stage, tumor burden, and patient fitness affect that choice?
In some cases, maintaining both ADC and bispecific programs against the same target may be justified; in others, it may lead to internal cannibalization and inefficient resource use.
Cell Therapies (CAR-T and Beyond)
CAR-T and related cell therapies use living immune cells as drugs. They have delivered transformative outcomes in several hematologic malignancies, though solid tumors remain challenging.
- Advantages: potential for deep and durable responses, long-lived immune memory.
- Challenges: cost and logistics, toxicity management, solid tumor penetration.
In relation to ADCs, important questions include:
- for shared targets (e.g., CD19, BCMA), which patients should receive ADCs vs cell therapies, and in what order?
- can ADCs be used as debulking tools before cell therapy to optimize outcomes?
Radiopharmaceuticals and Radiolabeled Antibodies
Radiopharmaceuticals, including α- and β-emitting agents, can be thought of as “radiation-based cousins of ADCs” that deliver ionizing radiation instead of chemical payloads.
- Advantages: highly localized DNA damage with short-path radiation, particularly for α-emitters.
- Challenges: radioisotope supply, radiation safety, specialized manufacturing and distribution.
Portfolio questions include whether to pursue:
- both an ADC and a radiolabeled antibody for the same target,
- or to choose between them based on target biology, tumor microenvironment, and practical constraints.
Small Molecules and Oral Therapies
Finally, small-molecule oral therapies remain foundational in many oncology settings:
- they are well suited to chronic, maintenance-style regimens,
- manufacturing and pricing can be more scalable in the long run.
A useful mental model is to view ADCs as “high-impact weapons” and oral small molecules as “logistics and long-term supply lines” within the same therapeutic campaign.
Three Levels of Portfolio Design Involving ADCs
Level 1: Mapping Diseases, Targets, and Modalities
The first step is to build a disease–target–modality matrix:
- which targets are biologically and clinically relevant in each indication,
- which modalities (ADC, bispecific, cell therapy, radiopharmaceutical, small molecule) are conceptually best suited,
- how current standards of care might evolve and interact with these modalities.
At this stage, the key is to avoid starting with “ADC everywhere” and instead let biology, clinical logic, and health economics drive modality choices.
Level 2: Life-cycle and Treatment-sequence Design
Next, ADCs must be placed within treatment lines and life-cycle strategies:
- Are ADCs intended for first-line use, or for later lines after standard regimens fail?
- Should we sequence ADC → bispecific → cell therapy for a given target, or switch targets along the way?
- What does the “exit plan” look like when resistance or toxicity emerges?
Whether ADCs are used as early debulking agents or as last-resort options has major implications for the required safety–efficacy profile and competitive positioning.
Level 3: Company-level Risk and Return Management
Finally, at the enterprise level, companies must manage modality concentration risk:
- what fraction of pipeline assets and R&D spend is devoted to ADCs,
- how internal ADC projects and in-licensed ADCs are balanced,
- how much optionality is preserved in non-ADC modalities for the 2030s and beyond.
In this sense, avoiding over-exposure to ADCs is itself a strategic asset, even for companies that are currently benefiting from the ADC wave.
Evaluating Modality Mixes: A View from Investors and Advisors
Question 1: Is the Company’s Modality Profile Over-skewed to ADCs?
For investors and advisors, a first diagnostic question is: “How heavily is this company’s future tied to ADCs?”
- In the short term, ADC headlines may drive valuation and sentiment.
- In the long term, sustainable growth often depends on a balanced modality mix.
For companies using ADCs to patch near-term patent cliffs, it is also important to ask what happens when today’s ADCs themselves approach cliff territory in the 2030s.
Question 2: Are Clear “Exits” Defined for Each Modality?
A second question is whether each modality has a clearly defined “exit” plan:
- if ADCs underperform, which modalities will support the portfolio?
- if ADCs perform better than expected, how will investments in other modalities be protected from crowd-out?
Companies that articulate such if–then structures tend to manage modality risk more effectively than those whose strategy is framed purely around the momentum of the current wave.
My Reflections
Whenever a modality captures market attention, there is a temptation to treat it as the answer to everything. ADCs are no exception. Yet over the time horizons that matter for cancer patients and for R&D organizations, concentrating too heavily on a single modality is risky. Even for the same target and indication, the optimal choice among ADCs, bispecifics, cell therapies, radiopharmaceuticals, and small molecules can differ depending on disease stage, tumor biology, clinical infrastructure, and economic realities. The most robust strategies therefore start from a portfolio view: Which segments truly call for ADCs, and where are other modalities better suited?
Importantly, the success of ADCs does not mean other modalities will fade away. If anything, ADC advances expand the design space for combinations and sequences— for example, using ADCs to debulk tumors before cell therapy, or combining ADCs with checkpoint inhibitors or bispecifics in rational ways. I suspect the real competition over the next decade will not be “ADC vs non-ADC”, but rather which organizations can best orchestrate multiple modalities into coherent, patient-centered treatment pathways. In that sense, technical excellence in ADCs is necessary, but not sufficient; what will differentiate leaders is the quality of their overall portfolio design.
This article has been edited by the Morningglorysciences team.
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