At its core, ADC design is an exercise in balance: the conjugate must remain stable in systemic circulation while releasing its payload efficiently once inside the target cell. Tip too far toward stability and the drug never activates; too far toward release and toxicity escapes into the bloodstream. Few recent programmes illustrate the careful management of this balance as clearly as SKB264 (sacituzumab tirumotecan), a TROP2-targeting ADC from Kelun-Biotech that introduced several meaningful structural advances over earlier ADCs in its class.

It is worth walking through them, because each component reflects a deliberate chemical decision.

The Payload: Permeability by Design

SKB264 carries KL610023, a belotecan-derived topoisomerase I inhibitor engineered with high membrane permeability. That permeability is not incidental — it promotes a strong bystander effect, allowing released payload to diffuse into neighbouring tumour cells. In heterogeneous solid tumours, where antigen expression varies from cell to cell, this ability to reach beyond the directly targeted cells is a significant advantage.

The Linker: Masking Hydrophobicity at High DAR

The linker combines a long PEG spacer with a pH-sensitive CL2A-carbonate moiety, and the design solves two problems at once.

The PEG chain addresses the hydrophobicity that comes with a high drug-to-antibody ratio (approximately 7.4). Loading that much payload onto an antibody would normally drive aggregation and poor pharmacokinetics, but the PEG masks that hydrophobicity — improving solubility, reducing aggregation, and supporting a more favourable PK profile.

At the same time, the flexibility of the PEG spacer improves accessibility of the cleavable group once the ADC is internalised into acidic lysosomal compartments, where the pH-sensitive carbonate is designed to release the payload. One spacer, two jobs: physicochemical masking in circulation and efficient presentation of the trigger inside the cell.

The Real Innovation: Conjugation Chemistry

The most significant advance in SKB264 lies in how the payload is attached to the antibody in the first place.

Classical ADC conjugation relies on maleimide-thiol linkages, which carry a well-known liability: they are prone to retro-Michael deconjugation in circulation. When that happens, payload is shed prematurely, producing off-target toxicity and eroding the therapeutic window.

SKB264 sidesteps this entirely. It uses a 2-methylsulfonyl pyrimidine moiety that forms an irreversible bond with antibody thiols through nucleophilic aromatic substitution. Because the linkage is irreversible, the retro-Michael pathway is simply not available — the payload stays attached until it is meant to be released.

A Chemistry With a Lineage

What makes this especially interesting is the provenance of the chemistry. The heteroaryl sulfone approach traces back to Pfizer, which patented heteroaryl sulfones for ADC conjugation in 2017. That work itself built on earlier academic studies exploring similar chemistry for the covalent stabilisation of mutant p53 proteins. Pfizer recognised that irreversible aromatic substitution could offer a substantially more stable alternative to classical maleimide linkages.

Kelun-Biotech was then the first to implement the strategy clinically through SKB264, demonstrating its pharmacokinetic and stability advantages in humans — moving the concept from patent to patient.

More recently, MediLink Therapeutics adopted the same pyrimidine conjugation anchor as the foundation of its TMALIN platform, pairing it with a highly hydrophilic dual-cleavage peptide linker designed for activation both intracellularly and within the tumour microenvironment. A single conjugation innovation has thus begun to seed multiple next-generation platforms.

The Broader Lesson

SKB264 is a useful case study because no single component carries it. The permeable payload, the dual-purpose PEG linker, and the irreversible conjugation anchor each address a specific failure mode of earlier ADCs — and they only deliver their advantage in combination. This is what the maturing of ADC design looks like: advances in conjugation chemistry, linker engineering, and payload design converging to reshape what the next generation of conjugates can achieve.

How SigutLabs Can Help

This is precisely the territory SigutLabs works in. We specialise in the rational design and synthesis of advanced linker-payload systems, helping developers address the stability, conjugation, and efficacy challenges at the heart of next-generation ADC programmes:

• Stable conjugation chemistries, including irreversible and site-specific approaches
• Linker design that balances circulation stability with efficient intracellular or tumour-microenvironment release
• Payload engineering for permeability, bystander activity, and drug-like properties

If you are working to overcome conjugation or stability challenges in an ADC programme, we would be glad to connect.

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