Non-cleavable Linkers: Permanently Linked, for Better or for Worse

Often overlooked, non-cleavable linkers are an important tool in antibody–drug conjugate (ADC) discovery. This chapter discusses the use of non-cleavable linkers in the context of ADCs. Non-cleavable linkers have the advantage of being able to modulate the activity of the metabolite through modifications such as changing membrane permeability, potency, or affinity to transporters. Since non-cleavable linkers are a part of the active metabolite, changes in the linker will alter the active metabolite. Non-cleavable linkers do not have membrane permeability, are more stable, and are usually better tolerated in pre-clinical studies than their cleavable counterparts. Many ADCs with non-cleavable linkers have gone into the clinic, but the vast majority has utilized only two constructs (MCC-DM1 and mc-MMAF). Different platform toxicities such as liver toxicity (MCC-DM1) and ocular toxicity (mc-MMAF) have been observed; nonetheless, two ADCs using these non-cleavable linkers have been approved. This area has been relatively unexplored compared to cleavable linkers, and this chapter will discuss how the use of non-cleavable linkers can be an important tool in ADC discovery.