Antibody-drug conjugates (ADCs) represent a transformative class of targeted cancer therapeutics that combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads to selectively eliminate tumor cells while sparing healthy tissue. An ADC comprises three essential components: a tumor-targeting antibody, a cytotoxic payload, and a linker that ensures drug release occurs precisely at the intended site. With the global ADC market projected to grow from USD 7.82 billion in 2022 to over USD 17 billion by 2030, there is an increasing demand for innovative and scalable technologies to support the development of next-generation ADCs.
While recent clinical successes have generated strong momentum in the biopharmaceutical sector, the structural complexity and multicomponent nature of ADCs continue to pose significant challenges—particularly around safety, manufacturability, and cost. In particular, the synthesis of structurally diverse linker-payload constructs remains laborious and low-yielding, which hinders broader clinical and commercial translation.
In this work, we introduce a late-stage on-resin desulfurization strategy that enables the synthesis of cleavable linkers entirely on solid support. This approach represents a significant advancement over traditional solution-phase and previously reported solid-phase methods. Our streamlined strategy allows for the efficient assembly of functionalized linkers and the direct incorporation payloads on resin. This not only improves overall yields but also enhances safety by minimizing handling of cytotoxic compounds in solution.
Together, this platform offers a practical and scalable solution for constructing complex linker-payloads, contributing to safer and more efficient ADC development. It exemplifies how peptide chemistry and solid-phase methodologies can be harnessed to address longstanding challenges in bioconjugation and targeted cancer therapy.
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2. Tong, J. T.; Sarwar, M.; Ahangarpour, M.; Hume, P. A.; Williams, G. M.; Brimble, M. A.; Kavianinia, I., Use of a Cyclic α-Alkylidene-β-Diketone as a Cleavable Linker Strategy for Antibody-Drug Conjugates. Journal of the American Chemical Society 2024, 146, 34, 23717–2372
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