Science & Technology

Antibody-drug conjugates (ADCs) are reshaping the oncology landscape by combining the targeting precision of monoclonal antibodies with the potency of cytotoxic payloads. However, as ADC payloads become increasingly potent and hydrophobic, developers are encountering growing challenges that affect both drug performance and manufacturability, including aggregation, reduced solubility, and instability.

These issues are frequently observed during ADC process development and scale-up. Across multiple ADC programs, payload-driven hydrophobicity can impact conjugation efficiency, product stability, purification behavior, and overall process robustness, making it a key factor influencing the developability and manufacturability of next-generation ADCs.

As biotech companies pursue alternatives that can improve the pharmacokinetic profiles of today’s more potent therapeutics, linkers with better physicochemical properties than the conventional linkers that were mainstays in early ADC applications are attracting attention. As a result, hydrophilic linkers capable of counteracting some of the inherent hydrophobicity of ADC payloads have emerged as enabling solutions for advancing increasingly complex and highly hydrophobic payloads.

Hydrophobicity, which has the potential to negatively impact both a drug’s developability and its ultimate safety and potency, has become a growing concern in ADC development as organizations work to conjugate more hydrophobic cytotoxic payloads to a single antibody. Low DAR can reduce payload delivery per antibody and compromise potency, whereas excessively high DAR may worsen physicochemical properties (e.g., hydrophobicity/aggregation), leading to faster systemic clearance, reduced exposure, and an increased risk of toxicity and immunogenicity.

Designed to improve solubility and mitigate issues that can arise from payload-derived hydrophobicity, hydrophilic linkers have consequently proliferated in the market. Options such as polyethylene glycol (PEG)-based linkers can enhance ADC performance, paving the way for a wider pipeline and greater commercial potential.

Yet many of these linker formats come with their own challenges, including cost considerations, synthesis complexity, and biocompatibility, which can complicate development in unique ways.

As ADC pipelines expand, hydrophilic linker design has become central to optimization efforts. Designed to address both hydrophobicity in ADC development and the challenges associated with other hydrophilic linkers, SoluFlex Link™ offers developers more favorable physicochemical and pharmacological properties for their therapeutics within an end-to-end ADC development platform.

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