The ADC arms race: payload power vs targeting precision

Over the past decade, antibody-drug conjugates (ADCs) have emerged as a high-impact class of cancer therapies, blending the selectivity of antibodies with the potency of cytotoxic payloads. But as the modality matures, a structural tension is becoming clear: should innovation focus on chemical escalation of payloads and linkers, or on biological precision of target engagement?

According to multiple industry sources, as described in a 2025 review of ADC pipeline trends, most next-generation ADC programmes over the last five years have poured resources into more potent warheads, improved linker stability, and novel conjugation technologies to increase efficacy while attempting to manage systemic toxicity.

However, a preview of data from platforms such as Promatix’s PBS293-MMAE — a dual-target, cis-bispecific ADC presented at the World ADC London Summit — suggests the next wave of innovation may be less about stronger cytotoxins and more about biological selectivity. This approach hinges on the ability to discriminate tumour cells based on combinations of surface antigens rather than single markers.

Payload escalation: the traditional track

Historically, ADC evolution has relied on three engineering pillars:

1. Antigen selection — choosing targets with high tumour expression.

2. Linker chemistry — optimising stability and release kinetics.

3. Payload potency — deploying extremely cytotoxic “warheads” to ensure cell kill.

As noted in clinical reviews of ADC efficacy and limitations, this strategy has produced approved ADCs such as brentuximab vedotin and trastuzumab emtansine, which demonstrate clear clinical efficacy in haematologic malignancies and certain solid tumours, respectively. But as ADCs expanded into broader oncology indications, the industry encountered recurring challenges: on-target/off-tumour toxicity, narrow therapeutic windows, and heterogeneous tumour antigen expression.

Biological precision: the emerging contender

Dual-target constructs like PBS293-MMAE flip the paradigm. Instead of increasing cytotoxic intensity, they engineer selectivity logic — binding only when two antigens are present together. This reduces collateral damage to healthy tissues that express either antigen alone, theoretically widening the therapeutic window.

This conceptual shift marks a departure from chemical escalation toward biological precision. While potent payloads remain important, the promise of bispecific ADCs lies in their ability to enhance discrimination between cancerous and normal cells. If clinical results follow preclinical signals, this innovation could sharpen ADCs’ competitive edge in solid tumours — the area where conventional approaches have struggled most.

This broadens commercial opportunity and changes how programmes are valued in early licensing discussions. Companies with capabilities in antigen-pair discovery, high-throughput proteomics, and biologically rational target design may attract increased partnership and capital. Early clinical validation will be the critical litmus test for whether biological logic translates into superior patient outcomes.

As the ADC field evolves, you’re now watching two dynamic vectors:

• Chemical innovation, which pushes cytotoxin and linker boundaries

• Biological innovation, which sharpens target engagement logic

The winners in the coming decade may not be those who simply make payloads stronger — but those who make them smarter.