Challenges and approaches to the design of hydrophilic linkers for antibody-drug conjugates.

Antibody-drug conjugates (ADCs) are now established approaches to the development of precision-guided therapeutics, yet some of the clinical translation effort has been constrained by a paradox at the heart of their design, that is the most effective cytotoxic payloads are also among the most hydrophobic. This intrinsic physicochemical mismatch - between a hydrophilic biological carrier and a hydrophobic small-molecule payload - continues to challenge the stability, pharmacokinetics, and therapeutic index of ADCs. Incorporation of hydrophilic linker architectures has therefore emerged as a critical strategy to counterbalance payload-associated hydrophobicity and enhance overall biophysical and biological performance. Here we examine these approaches within a systematically organized and conceptually unified framework that categorizes hydrophilic linker design according to the strategic placement of solubilizing elements along the linker-payload continuum, as illustrated in Fig. 1. Specifically, potential sites for hydrophilic group incorporation - listed in order of increasing distance from the antibody - include the antibody attachment region, the linker spacer, and the payload release site. Each section of the review surveys representative literature examples within one of these spatial domains, highlighting both established and emerging design principles and elucidating key structure-function relationships governing ADC stability, pharmacokinetics, and controlled payload release. Major classes of hydrophilic motifs, including polyethylene glycol (PEG) chains, zwitterionic structures, carbohydrate-based moieties, and next-generation water-solubilizing scaffolds, will be discussed in a comparative manner. We will also demonstrate how we conceive our internally developed patented hydrophilic linker architecture as an illustration for potential future directions. STATEMENT OF SIGNIFICANCE: We reviewed the principles of ADCs linkers and shared our perspectives on the challenges and innovative approaches to the future ADC drug development.