Antibody-drug conjugates (ADCs) have transitioned from an experimental concept to a core oncology modality, driven largely by advances in payload and linker technologies. While early ADC programs were hindered by instability, narrow therapeutic indices, and manufacturing complexity, recent progress in linker chemistry and high potency payload handling has enabled a new generation of clinically viable candidates. As pipelines expand and competition intensifies, payload-linker engineering has become a key determinant of both clinical performance and manufacturability.

The fundamental premise of ADCs—selective delivery of a potent cytotoxic agent via an antibody—has remained unchanged for decades. However, the technical execution has evolved significantly. After the first ADC approval in 2000, progress remained slow for nearly two decades. More recently, improvements in linker stability, payload diversity, and conjugation strategies have catalyzed a rapid increase in ADC approvals, clinical programs, and large-scale partnering activity.

Between 2018 and 2023, the number of ADCs in clinical development grew by more than 30%, reflecting growing confidence in the modality and the maturation of enabling technologies. The growth continues. Industry reports indicate that by 2025 there were more than 200 clinical-stage ADC programs across all phases, with a growing number advancing to Phase III as developers pursue differentiated mechanisms of action and refined payload-linker systems.

Linker Chemistry and Its Impact on ADC Performance

The linker is a critical component of any ADC, directly influencing pharmacokinetics, safety, efficacy, and manufacturing robustness. An optimal linker must exhibit high plasma stability to prevent premature payload release, while enabling efficient payload liberation at the target site through predictable and reproducible mechanisms.

Linkers are typically classified as cleavable or non-cleavable. Cleavable linkers are designed to respond to tumor-associated triggers such as lysosomal enzymes, reductive environments, or acidic pH. Common examples include peptide-based linkers cleaved by cathepsins and disulfide linkers sensitive to intracellular reducing conditions. These systems can support bystander killing effects, which may be advantageous in heterogeneous solid tumors.

Non-cleavable linkers rely on complete internalization of the ADC followed by lysosomal degradation of the antibody to release an active payload-linker residue. While this approach generally provides enhanced systemic stability and reduced off-target toxicity, it can limit payload selection and may reduce efficacy in indications where tumor penetration and payload diffusion are critical.

Beyond the cleavable versus non-cleavable distinction, linker design must account for factors such as hydrophobicity, drug-to-antibody ratio (DAR), conjugation site compatibility, and downstream analytical characterization. Small variations in linker structure can have outsized effects on aggregation, clearance, and batch-to-batch consistency.

Custom Payload-Linkers and High Potency Manufacturing Considerations

As ADC targets become more crowded, reliance on standardized, commercially available payload-linker constructs is increasingly viewed as a limitation. Custom payload-linker design enables sponsors to optimize conjugate stability, payload release kinetics, and therapeutic index for specific biological targets. These efforts, however, introduce additional manufacturing complexity.

Many ADC payloads are highly potent active pharmaceutical ingredients (HPAPIs) with occupational exposure limits in the low nanogram per cubic meter range. Safe and compliant synthesis of payload-linkers requires purpose-built containment strategies, specialized purification technologies, and experienced development and manufacturing teams.

From a CMC perspective, payload-linker manufacturing must support efficient scalability, impurity control, and overall reproducibility to align with GMP consideration. Key considerations include:

• Synthetic routes that aim to minimize handling of payload and support robust impurity control
• Purification strategies such as preparative HPLC or controlled crystallization 
• Analytical methods capable of resolving structurally similar impurities
• Stability profiles that support downstream conjugation and storage

Facilities suitable for the handling of both standard and highly potent or cytotoxic payload-linkers are increasingly important as ADC programs progress from early clinical phases toward commercialization.

Integration Across the ADC Value Chain

Fragmented ADC development models—where payloads, linkers, antibodies, conjugation, and fill/finish are sourced from multiple vendors—can introduce coordination challenges, extended timelines, and increased technical risk. In response, many sponsors are seeking more integrated development and manufacturing approaches.

An integrated ADC model allows parallel development of payload-linkers, antibodies, bioconjugation processes and formulation of the drug product, reducing overall cycle time and improving alignment between development and clinical requirements. Access to upstream capabilities for intermediates and downstream services such as conjugation and sterile fill/finish can further streamline execution.

From a manufacturing standpoint, early integration supports:

• Faster transition from non-GMP to GMP material
• Improved control over critical quality attributes
• Smoother scale-up through coordinated process development
• Reduced technology transfer complexity between sites and vendors

As the use of ADCs expands to include alternative targeting moieties, multi-payload constructs, and novel conjugation chemistries, this level of coordination becomes increasingly valuable.

Preparing for Late-Stage Development and Commercialization

With a growing number of ADCs advancing into late-stage clinical development, attention is shifting toward commercial readiness. Payload-linker processes developed for early-stage supply must ultimately support larger batch sizes, consistent quality, and regulatory compliance across global markets.

Experience with regulatory filings, process validation, and lifecycle management is therefore an important consideration when selecting development and manufacturing partners. Facilities with established track records in HPAPI manufacturing and ADC-related regulatory submissions are better positioned to support long-term program success.

Payload-Linker Expertise in the USA

Piramal Pharma Solutions is empowering its partners to succeed in the ADC market. Working out of its Riverview, Michigan drug substance site, the company provides custom, non-commercially available payload-linkers. Most of the payload-linkers manufactured within our facilities are crafted based on the client’s structure or are related to an existing platform technology that Piramal can access via active partnerships. By developing and manufacturing the right material for each project, Piramal is helping companies to stand out in a competitive landscape. 

The Riverview site has dedicated laboratories to handle the HPAPI payload-linker assembly and purification. Using either permanent or disposable isolators, the facility supports manufacturing to approximately 400g of material when preparative purification is required and up to multi kilograms when the process calls for other purification procedures. Piramal has equipped the site to perform chemical synthesis in up to 50L reactors, purifications by flash chromatography, and preparative-scale HPLC in addition to isolation by traditional precipitation/crystallization methods or lyophilization. 

The site is currently expanding its HPAPI facilities and bringing online a new 1070 square foot state-of-the-art laboratory, equipped to handle HPAPI as low as 10ng/m³. This includes investments in larger scale preparative HPLC equipment and lyophilization technologies to facilitate faster scale-up and shorter manufacturing cycles. The Riverview site has performed process research, development, optimization and scale-up for both standard and high potency payload-linkers and, overall, has worked on 20 FDA manufacturing approvals.

Piramal has deployed these capabilities to create a variety of linkers for delivering a wide range of payloads such as MMAE, glycosylated Auristatin, Exatecan, specific Pyrrolobenzodiazepines, and Doxorubicin. The broad structural diversity among linkers and payloads allows for numerous rational design strategies, supporting the tailored assembly of payload-linker constructs to meet specific therapeutic or functional objectives.

Conclusion

Payload-linker technology has emerged as a central driver of ADC differentiation, influencing not only clinical outcomes but also manufacturability and development timelines. As competition intensifies and ADC architectures grow more complex, sponsors are increasingly prioritizing custom payload-linker design and integrated manufacturing strategies.

For CDMOs and drug developers alike, continued innovation in linker chemistry, high potency processing, and end-to-end integration will be critical to sustaining momentum in the ADC space and delivering the next generation of targeted oncology therapies.