Antibody-Drug Conjugates (ADCs) are a rapidly growing class of anticancer agents comprising a small molecule cytotoxin and a monoclonal antibody (mAb). A covalent linker joins the two therapeutic components, the properties of which are crucial to the success of an ADC. Although cathepsin-cleavable dipeptides are the most widely used linker motifs, they suffer from a number of key drawbacks, such as instability in rodent blood and poor aqueous solubility. First, this thesis describes the design, synthesis and evaluation of arylsulfates as enzymecleavable ADC linkers. These arylsulfates were designed to be cleaved by lysosomal sulfatases, thus revealing a phenolate, primed for 1,6-elimination of a payload within the target cell (Figure 1A). Initially, a panel of model linkers were synthesised using a neopentyl sulfate protecting group. Upon analysis under physiological conditions, the linkers were revealed to be remarkably stable in human and mouse plasma, but cleaved by sulfatases to release their payload cargo. Each arylsulfate model linker demonstrated a vastly different rate of sulfatase-mediated hydrolysis, suggesting a variation in their in vitro payload release rates. Upon these encouraging outcomes, the arylsulfate motifs were elaborated to full linkerpayloads, incorporating an antibody-attachment handle and a potent cytotoxin. Conjugation to an antibody was then performed and the resulting ADCs were evaluated in both antigenpositive and -negative cells. Cell viability data revealed that certain arylsulfate-ADCs were highly cytotoxic and cell-selective, with a correlation between sulfatase-cleavage rate and potency. Thus the novel linkers described herein perform similarly to the commonly employed dipeptides, whilst exhibiting vastly superior plasma stability and aqueous solubility. It is anticipated that these arylsulfate linkers can be applied to a wide range of potential antibodies and payloads, especially given their synthetic accessibility. Second, a sulfated β-galactose-based linker-payload was investigated as an alternative cleavable group. The linker was designed to be initially cleaved by the lysosomal arylsulfatase A enzyme, followed by subsequent β-galactosidase hydrolysis and 1,6-elimination of the payload (Figure 1B). By exploiting this dual-enzymatic cascade, the linker was anticipated to be extraordinarily hydrophilic and lysosome-selective. Once synthesised, the sulfogalactose linker-payload was conjugated to an antibody in 100% aqueous media, demonstrating the solubilising effect of the sulfo-galactose group. The resulting ADC was evaluated in vitro, revealing similar potency and selectivity to the most toxic arylsulfate-ADC. Thus, the iv sulfo-galactose motif is also anticipated to be an effective enzyme-cleavable approach for a variety of ADC payloads and antibodies. The remarkable aqueous solubility renders the cleavable motif particularly suited to highly lipophilic payloads.