Types of Acid Labile Linkers

Common acid labile linkers feature diverse chemical structures and functional groups. Each type performs differently in pH-sensitive cleavable linker design, and selection must consider payload properties, plasma stability, and release kinetics.

Hydrazone-Based Linkers

Hydrazone linkers are among the most widely used acid labile linkers. They are typically formed by condensation of aldehydes or ketones with hydrazine groups (–NH–NH–). Acid labile hydrazone linkers efficiently release payloads through hydrolysis in acidic environments (pH 4.5–6.5). By introducing electron-donating or electron-withdrawing groups, their pH sensitivity and plasma stability can be finely tuned—stable in circulation while rapidly degrading inside target cells. Mature and scalable synthetic routes make hydrazone linkers suitable for large-scale GMP production. They are widely applied in ADCs such as the FDA-approved Mylotarg®. Current research focuses on developing more acid-sensitive hydrazone linkers to further improve plasma stability, minimize premature drug release, and enhance the therapeutic index.

Cis-Aconityl Linkers

Cis-aconityl linkers are formed by conjugating cis-aconitic acid with amines to create acid-sensitive amide bonds, releasing payloads via acid-catalyzed hydrolysis. Compared to hydrazone linkers, cis-aconityl structures offer improved plasma stability, making them ideal for ADCs requiring longer circulation times. Their pH-responsive behavior is predictable, and release rates are relatively stable, reducing non-specific release. However, synthesis is more complex, and compatibility with certain payloads may require optimization, increasing early development workload. Nevertheless, cis-aconityl remains a strong candidate for acid cleavable linker antibody design when extended in vivo circulation is desired.

Acetal and Ketal Linkers

Acetal and ketal structures are classic pH-sensitive cleavable linkers that rapidly hydrolyze under acidic conditions to produce corresponding alcohols and carbonyl compounds. They are particularly suitable for ADCs that require fast payload release within tumor cells, allowing cytotoxic effects to occur shortly after entry into endosomes or lysosomes. Hydrolysis rates can be precisely adjusted through steric modifications or substituent variation, providing highly controllable release kinetics. This makes them valuable for constructing efficient acid labile linkers for antibody-drug conjugates.

Orthoester Linkers

Orthoesters are versatile acid-labile linkers for antibody-drug conjugates. They decompose in acidic environments to form esters and alcohols, and byproducts can be designed as non-toxic or functional molecules. Orthoesters offer exceptional structural tunability, allowing precise control of pH responsiveness to match intracellular conditions and payload release requirements. They are compatible with both hydrophilic and hydrophobic payloads, and can be combined with other linkers to achieve dual-triggered drug release. In multifunctional acid cleavable linker antibody formulations, orthoester structures are often used as core design elements, providing rich chemical flexibility for personalized ADC development.