Combining the specificity of monoclonal antibodies with the potency of cytotoxic payloads, ADCs enable targeted delivery of therapeutics to diseased cells while minimising damage to healthy tissue. Over the past decade, growing clinical success and strong commercial performance have transformed the field, with ADCs now regarded as a core therapeutic modality within oncology and beyond.
Payload linker innovation is integral to this growth. The specialised chemical structures connect the targeting antibody to the therapeutic payload, playing a crucial role in determining stability, safety, efficacy, and manufacturability. As the ADC pipeline expands and competition intensifies, payload linker innovation is increasingly recognised as a key differentiator.
ADCs as a major therapeutic modality
According to GlobalData, the ADC market is expected to reach $65.2bn by 2031 as more products reach commercialisation. This growth reflects both increasing approvals and the rising commercial success of individual drugs. The pipeline is also expanding rapidly, with GlobalData reporting that the number of ADCs in development or on the market increased from 557 in 2020 to 1,643 by 2025, nearly tripling in just five years.
This momentum is, to a large extent, due to promising clinical trial data and successful market approvals of ADCs which have brought clear patient benefit. Several factors have enabled this success, including improvements in antibody engineering, conjugation techniques, and payload design, which have improved efficacy and reduced toxicity.
As ADC pipelines expand and new therapeutic formats emerge, attention has increasingly turned to one critical component of ADC design: the payload linker.
Understanding the role of payload linkers
Within an ADC, the linker is the chemical bridge that attaches the cytotoxic payload to the antibody. It must maintain stability during circulation in the bloodstream while enabling precise release of the payload once the ADC reaches its target cell. If the linker releases the payload too early, it can damage healthy tissue and reduce therapeutic effectiveness. Whereas if the linker is too stable, the payload may not be released efficiently within the target cell, limiting efficacy.
Linkers are categorised into two main types: cleavable and non-cleavable. Cleavable linkers are designed to release the payload in response to specific biological conditions such as the presence of enzymes or changes in pH within the tumour microenvironment. Non-cleavable linkers remain intact until the ADC is internalised by the target cell and degraded within lysosomes, releasing the active drug.
Most approved antibody-drug conjugates utilise cleavable linkers which are designed to release the pharmacologically active cytotoxic payload under the correct conditions. This strategy bestows improved plasma stability of the ADC, while permitting release of the payload only after antigen binding and internalisation of the ADC by the target cell1.
Hydrazone linkers (acid-labile)
Hydrazone linkers were among the earliest linker technologies used in ADCs. These linkers are pH-sensitive and designed to break down in the acidic environments of endosomes and lysosomes following ADC internalisation. One of the earliest ADCs, gemtuzumab ozogamicin (Mylotarg), used a hydrazone linker to attach the calicheamicin payload to its antibody.
Although this approach demonstrated the feasibility of ADCs, hydrazone linkers proved not as stable as hoped, and premature cleavage in circulation contributed to safety concerns and drove the development of more stable linker systems.
Protease-cleavable peptide linkers
Peptide-based linkers are cleaved by tumour-associated proteases, particularly lysosomal enzymes such as cathepsin B. A widely used example is the valine-citrulline (Val-Cit) linker, employed in several successful ADCs, including brentuximab vedotin (Adcetris). In this system, the peptide linker is cleaved inside the tumour cell by proteases, releasing the potent auristatin payload.
The Val-Cit linker has become a widely adopted platform because it combines strong plasma stability with efficient intracellular release.
Disulfide linkers
Disulfide linkers exploit the difference in redox potential between extracellular and intracellular environments. In circulation, the disulfide bond remains relatively stable. However, once inside the cell, high concentrations of reducing agents such as glutathione break the bond and release the payload.
β-glucuronide and tumor microenvironment active linkers
More recently, developers have explored enzyme-activated linker systems that respond to enzymes present in the tumour microenvironment. These linkers can improve selectivity and may enable new ADC strategies that release drugs even before internalisation in some tumour environments. This design also supports the bystander effect, in which the released payload diffuses into neighbouring tumour cells that may not express the target antigen, thereby improving treatment effectiveness in heterogeneous tumours.
The latest research on payload linker innovation
Recent peer‑reviewed studies further highlight the critical role of linker chemistry in determining ADC performance. Medicinal chemistry analyses suggest that although linker-payload structures typically represent less than 500 Da of an ADC’s total molecular mass, they exert a disproportionate influence on pharmacokinetics, systemic stability, and therapeutic index. Improved linker design can significantly reduce premature payload release while enabling more controlled intracellular drug delivery2.
Comparative research examining linker functional groups has also shown that in‑vivo stability typically follows the order amide > carbamate > ester > carbonate. These findings demonstrate how relatively small structural differences in linker design can substantially influence the likelihood of premature drug release and systemic toxicity3.
To enable the traceless release of the pharmacologically active payload, a suitable chemical connectivity to the linker must be designed. Amides and carbamates are very suitable for connecting to amine functionalities on payloads. However, designing a suitable chemical linker to enable connection to a payload through an alcohol functionality is more synthetically challenging. A nice solution to this problem is the use of ortho-hydroxy-protected aryl sulfates (OHPAS)4. This greatly expands the payload linker design space to include payloads without amine functionalities.
Peptide‑based cleavable linkers remain dominant in many ADC designs, particularly those employing protease‑activated release mechanisms. Ongoing research is focused on improving plasma stability while maintaining efficient enzymatic cleavage within tumour cells. Optimisation of these peptide linker systems aims to enhance tumour‑specific activation while reducing off‑target toxicity5.
Researchers are also exploring multifunctional linkers capable of attaching multiple payloads to a single antibody. These dual‑payload systems have shown potential to improve tumour cell killing in heterogeneous tumours by combining different cytotoxic mechanisms within a single ADC construct6.
Next-generation linker strategies
Modern approaches being explored in these studies, such as engineered cysteine residues, enzymatic conjugation methods, and peptide-mediated conjugation technologies such as AjiCap7, enable payloads to be attached at defined sites on the antibody. These techniques enable more consistent drug-to-antibody ratio (DAR) values and improved stability.
Linker technologies are also evolving to support next-generation payload classes, including topoisomerase inhibitors, immune modulators, and targeted protein degraders. These payloads can be enhanced with specialised linker chemistries to achieve optimal release kinetics and therapeutic activity.
“In recent years, payload-linker innovation has focused on improving plasma stability, enabling controlled payload release, and reducing overall ADC hydrophobicity,” said Jean-Francois Carniaux, vice-president and Global API Technical Lead at Piramal Pharma Solutions. “Developers are also exploring linkers compatible with new payload classes beyond traditional microtubule inhibitors. While oncology remains the dominant application, growing interest is emerging in autoimmune disease and other therapeutic areas.”
Challenges in customised payload linker development
Despite the rapid progress in ADC technology, payload linker development remains technically complex. Small structural changes in linker design can influence conjugation efficiency, DAR, stability, and overall therapeutic performance.
The manufacturing of payload linkers also presents unique challenges. Because ADC payloads are typically highly potent compounds, they require specialised high-potency active pharmaceutical ingredient (HPAPI) facilities to ensure safe handling and containment during synthesis and scale-up.
According to Carniaux, custom payload linker development requires a combination of chemical expertise, advanced analytical tools, and specialised manufacturing infrastructure.
“Customised payload-linkers introduce challenges around synthetic complexity, stability, and safe handling of highly potent payloads during development and scale-up,” says Carniaux. “Small structural changes can also affect conjugation efficiency, manufacturability, and overall ADC stability.”
To overcome these challenges, developers increasingly rely on specialised contract development and manufacturing organisations (CDMOs) with dedicated capabilities in HPAPI chemistry and conjugation technologies.
The importance of specialist in payload linker manufacturing
As ADC pipelines expand, pharmaceutical companies are increasingly seeking partners with integrated capabilities across ADC development. Specialised expertise in both novel conjugation technologies, and complex HPAPI development and manufacture addresses two of the major challenges in ADC development.
Piramal Pharma Solutions has positioned itself in this evolving landscape through its specialised capabilities in payload linker development. The company produces custom payload linkers at its HPAPI facility in Riverview, Michigan, US, enabling developers to design tailored linker-payload constructs rather than relying on standard off-the-shelf materials.
The Riverview facility is equipped with specialised laboratories capable of handling highly potent compounds and performing chemical synthesis, purification, and isolation processes required for payload linker production.
As the ADC pipeline expands and requirements become more specific, innovations in linker chemistry and manufacturing will be essential.
To find out more about the specialist payload linker services provided by Piramal, download the document below.
References:
- https://pubmed.ncbi.nlm.nih.gov/40432256/
- https://pmc.ncbi.nlm.nih.gov/articles/PMC10953486/
- https://pmc.ncbi.nlm.nih.gov/articles/PMC12013038/
- https://pubs.acs.org/doi/10.1021/acs.bioconjchem.9b00341
- https://pubmed.ncbi.nlm.nih.gov/40891142/
- https://pmc.ncbi.nlm.nih.gov/articles/PMC12054377
- https://pubs.acs.org/doi/10.1021/acs.bioconjchem.3c00040
