MMAE vs. DXd: Can ADCs Still Compete?

Why the payload debate matters

Antibody-drug conjugates (ADCs) were designed to solve a long-standing problem in cancer treatment: how to deliver extremely potent cytotoxic drugs to tumors while limiting exposure in healthy tissues. Yet the antibody is only one part of the equation. The linker controls when and where the drug is released, while the payload determines what happens after the ADC reaches the target cell. As ADC development has matured, the choice of payload has therefore become a strategic decision rather than a simple chemistry preference. MMAE and DXd illustrate two particularly important approaches. MMAE, or monomethyl auristatin E, is a highly potent microtubule-disrupting payload that has been incorporated into multiple clinically successful ADCs. DXd, the exatecan-derived payload used in trastuzumab deruxtecan and other ADC programs, inhibits topoisomerase I and damages DNA during replication. Both can deliver potent antitumor activity, but they create very different pharmacological profiles. The question is therefore not simply whether DXd is "better" than MMAE. The more useful question for ADC developers is whether MMAE-based designs can still offer a competitive therapeutic window when newer topoisomerase I inhibitor payloads have demonstrated strong activity in solid tumors. The answer is yes—but only when the antibody, linker, conjugation strategy, payload exposure and target biology are engineered as one integrated system.

DXd: why the newer generation changed expectations

DXd represents a different pharmacological strategy. It is an exatecan derivative that inhibits topoisomerase I, interfering with the DNA replication process and ultimately generating lethal DNA damage. This mechanism differs fundamentally from the microtubule disruption produced by MMAE, which means the two payloads can behave differently depending on tumor proliferation, DNA-repair capacity, intracellular trafficking and resistance mechanisms.

DXd has become especially influential because it is associated with ADC designs capable of producing substantial activity across a range of solid tumors. Trastuzumab deruxtecan, for example, contains approximately eight deruxtecan molecules per antibody and uses a protease-cleavable tetrapeptide linker. This relatively high drug loading, together with the properties of the released payload, contributes to a strong pharmacological effect and a pronounced bystander component.

The clinical momentum behind DXd is also difficult to ignore. In 2026, the FDA expanded trastuzumab deruxtecan into two additional HER2-positive early-stage breast cancer settings, demonstrating how rapidly DXd-based ADC technology continues to influence treatment strategies.

But DXd is not a universal solution. Its potency and broad tissue activity do not eliminate the fundamental challenges of ADC development. Trastuzumab deruxtecan, for example, carries a boxed warning for interstitial lung disease and pneumonitis, including fatal cases. This is an important reminder that increasing payload delivery does not automatically produce a wider therapeutic window.

The linker can change the answer

One of the most overlooked issues in an MMAE-versus-DXd comparison is that payload performance cannot be separated from linker design. A highly potent payload is only useful if the ADC remains sufficiently stable in circulation and releases the active drug efficiently after reaching the intended intracellular environment.

For MMAE, cleavable linkers have been extensively explored because controlled intracellular release can generate membrane-permeable MMAE and enhance bystander killing. The challenge is maintaining adequate plasma stability while achieving efficient release inside target cells.

DXd-based ADCs have similarly relied on carefully engineered cleavable linkers. The current generation of designs demonstrates how linker-payload combinations can support high drug loading without simply accepting uncontrolled systemic release. This is one reason why payload comparisons based only on the free drug can be misleading: the pharmacology of an ADC is determined by the complete antibody-linker-payload architecture.

Where DXd has raised the bar

The challenge for MMAE is that DXd has changed expectations for what an ADC can accomplish in solid tumors. DXd-based platforms have demonstrated that high payload loading, potent intracellular activity and bystander effects can be combined into clinically meaningful therapeutic designs. This has pushed ADC developers to think beyond the traditional model of simply maximizing potency.

However, the success of DXd also highlights the importance of safety engineering. Greater payload delivery can increase efficacy but may also expose normal tissues to biologically active drug. The clinically recognized risk of interstitial lung disease and pneumonitis with trastuzumab deruxtecan is a clear example of why ADC development must balance tumor killing with systemic tolerability.

For this reason, "DXd is more powerful" is not sufficient as a development strategy. The relevant endpoint is the therapeutic index: how much antitumor activity can be achieved relative to toxicity, exposure and treatment limitations.

What ADC developers should evaluate

When deciding between MMAE and DXd, development teams should consider the complete product profile rather than payload potency in isolation. Target expression and internalization should be examined alongside linker stability, intracellular release, DAR, plasma exposure, bystander activity, tissue distribution and the expected resistance mechanisms.

The practical lesson is straightforward: MMAE is not losing because DXd exists, and DXd is not automatically superior because it is newer. Their value depends on the biological problem the ADC is being designed to solve. The strongest programs will be those that use payload selection as part of a rational engineering strategy rather than treating the payload as an interchangeable component.

For researchers developing next-generation ADCs, this distinction is increasingly important. As ADCs move toward more sophisticated targets, higher drug loading, site-specific conjugation and increasingly complex tumor indications, the winning molecule will be defined less by the name of its payload and more by how effectively the entire construct converts target recognition into selective tumor killing.

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