Linkers

The linker is a foundational design element in modern drug development, serving as a molecular bridge that connects pharmacologically distinct components within a single therapeutic agent. In antibody-drug conjugates (ADCs), the linker connects a cytotoxic payload to a monoclonal antibody, ensuring stable attachment in circulation and enabling targeted delivery to tumour cells while minimising off-target effects; it substantially impacts the therapeutic index, efficacy, and pharmacokinetics of these drugs. Beyond ADCs, linkers are equally central to the architecture of proteolysis-targeting chimeras (PROTACs), PEGylated proteins, and peptide-lipid conjugates. In each context, the linker must satisfy competing demands: sufficient plasma stability to prevent premature release, and sufficient lability or trigger-responsiveness to release the active payload at the intended intracellular or biological site. Linkers vary considerably in composition, including alkyl chains, polyethylene glycol (PEG) units, peptide sequences, disulfide bonds, and hydrazones. In ADCs, the choice of linker type determines whether release is cleavable (via enzymes, pH, or reducing environment) or non-cleavable (requiring full lysosomal degradation of the antibody). Most approved ADCs employ cleavable peptide linkers that are hydrolysed by enzymes such as cathepsin, plasmin, or legumain, balancing stability in the circulatory system with selective release of the cytotoxic payload in tumour tissue. The pharmacological diversity enabled by linker technology has transformed drug design, converting otherwise too-toxic molecules into precisely delivered therapeutics and bringing previously undruggable targets within reach.

Two commercially transformative drugs demonstrate the breadth of linker application across molecular classes. Semaglutide (Ozempic/Wegovy, Novo Nordisk), the GLP-1 receptor agonist and world-leading revenue drug, achieves its once-weekly pharmacokinetic profile through a linker-based lipidation strategy. Semaglutide's main protraction mechanism is albumin binding, facilitated by modification of the position 26 lysine with a hydrophilic spacer connected to a C18 fatty diacid, extending its half-life to approximately one week. Semaglutide accounted for approximately USD 26.68 billion in sales in 2024, making it the highest-grossing drug globally and a direct demonstration of linker-optimised pharmacokinetics at commercial scale. Trastuzumab emtansine (Kadcyla, Roche/Genentech) illustrates the ADC application of linker design. Kadcyla uses the non-cleavable SMCC thioether linker to attach the potent microtubule inhibitor DM1 to trastuzumab via lysine residues, with an average drug-to-antibody ratio of 3.5 DM1 molecules per antibody. Launched in 2013 as the first ADC approved for a solid tumour, Kadcyla generated approximately USD 2.3 billion in global sales in 2024.

Three first-in-class approvals illustrate the continued innovation in linker-based therapeutics. Mirvetuximab soravtansine (Elahere, AbbVie/ImmunoGen) is a first-in-class ADC targeting folate receptor alpha (FRα), comprising an FRα-binding antibody, a cleavable sulfo-SPDB disulfide linker, and the maytansinoid payload DM4; it received full FDA approval in March 2024 for platinum-resistant ovarian cancer. The sulfo-SPDB linker is specifically designed to counteract multidrug resistance through a disulfide-containing cleavage mechanism that prevents premature release in the bloodstream while enabling intracellular payload release following internalisation. Datopotamab deruxtecan (Datroway, Daiichi Sankyo/AstraZeneca), approved in 2025 as the first TROP2-directed therapy for EGFR-mutated non-small cell lung cancer, employs tetrapeptide-based cleavable linkers to conjugate multiple DXd topoisomerase I inhibitor payloads to a humanised anti-TROP2 IgG1 antibody. This tetrapeptide linker enables a high drug-to-antibody ratio and pronounced bystander killing effect upon lysosomal cleavage. Vepdegestrant (Veppanu, Arvinas/Pfizer), approved in May 2026, is the first-and-only FDA-approved PROTAC, a heterobifunctional protein degrader in which a heterocycle-rigidified linker bridges an estrogen receptor binding ligand to a cereblon-recruiting moiety, directing polyubiquitination and proteasomal degradation of ESR1-mutated ER in advanced breast cancer.

PROTACs exemplify the most sophisticated current use of linkers in small-molecule drug design. PROTAC protein degraders are heterobifunctional small molecules comprising two domains: one that binds a target protein and another that engages an E3 ubiquitin ligase joined by a linker; simultaneous engagement of both proteins enables ubiquitination and subsequent proteasomal degradation of the target. Flexible alkyl-based and PEG-based linkers account for the majority of linker types in reported PROTACs at 44.81% and 22.85%, respectively, with more rigid linkers representing a growing minority as structure-activity studies reveal that linker geometry directly governs the ternary complex conformation required for productive ubiquitin transfer. Beyond PROTACs, molecular glues, LYTAC (lysosome-targeting chimeras), and ATTEC (autophagy-targeting chimera) platforms all rely on linker architecture to direct the degradation of proteins, nucleic acids, and aggregated structures. PEG linkers remain the most commonly deployed hydrophilic spacers, chosen for their low immunogenicity, water solubility, and capacity to shield hydrophobic payloads from aggregation and premature immune recognition during systemic circulation. The field of linker design, sometimes called "linkerology", is now a discipline in its own right, with the geometry, rigidity, polarity, and cleavage chemistry of the linker recognised as determinants of efficacy, selectivity, and safety that are at least as important as the choice of targeting ligand or cytotoxic payload. For the medicinal chemist, the linker is no longer a passive connector but an active pharmacological component whose optimisation can determine whether a therapeutic concept reaches clinical approval.