The ADC linker serves as a crucial "bridge" component.

In the realm of antibody-drug conjugates (ADCs), linkers are the unsung heroes. Primarily, linkers connect hydrophilic antibodies to typically hydrophobic drug carriers. Upon entering the human body, linkers maintain this connection until the ADC enters cells; only then do they completely dissolve, releasing the drug payload to initiate its therapeutic action. Despite their critical role, linkers are often overlooked. When discussing ADCs, the first aspects that come to mind are typically antibody targeting and cytotoxic payload delivery. While antibodies and payloads are indeed present, this does not imply that issues such as hydrophobicity, poor pharmacokinetic properties, or aggregation have been resolved—far from it. As the development scale of antibody-drug conjugates (ADCs) expands, attention to linker design and utilization becomes paramount for ensuring ADC safety, stability, and efficacy.

ADC设计和作用机制.png

Figure 1 ADC Design and Mechanism of Action

A "linker" skilled at establishing connections often breaks down barriers.

Given that the payload of an ADC may be toxic, safety remains a critical concern. A potent linker maintains ADC stability in the bloodstream, preventing premature release of the payload and thus avoiding severe off-target effects. However, this binding is not permanent: once the ADC enters target cells, lysosomes degrade the peptide chains in the linker, releasing the drug payload. Crucially, while the linker system degrades under certain lysosomal enzymes, it remains stable in the circulatory system; more importantly, the linker must not only dissociate but also self-degrade. Even minimal residual linker components could significantly impair therapeutic efficacy.

The linker also plays another critical role by modulating the interaction between the ADC and water. Hydrophobic payloads may adversely affect the pharmacokinetics of the ADC, thereby limiting its therapeutic efficacy. Hydrophobic regions can also lead to ADC aggregation and attract immune system recognition. Pharmaceutical companies typically coat the linker with hydrophilic compounds (such as polysarcosine or polyethylene glycol [PEG]) to counteract the hydrophobicity of the payload and align it more closely with the natural hydrophilicity of the antibody. This hydrophilic coating enhances both the efficacy and safety of the ADC. PEG and polysarcosine provide a shielding hydrophilic effect, which is essential for certain payloads. Traditional cytotoxic molecules are generally highly hydrophobic, while protein degradation agents exhibit extreme hydrophobicity; in contrast, oligonucleotides (e.g., siRNA) possess strong hydrophilicity. Therefore, linker design largely depends on the specific payload.

This dependency drives the logical progression of ADC development. First, the payload should be selected based on which target molecules are effective for specific indications. The payload determines the drug-to-antibody ratio (DAR), which influences stability, pharmacokinetics, aggregation, and ultimately therapeutic efficacy. For conventional cytotoxic payloads, the hydrophobicity must be mitigated to a certain extent using linkers.

Challenges posed by ADCs with chemical properties

Addressing ADCs presents significant challenges at every stage. During early-stage development, laboratories handle only trace amounts of drug-linker mixtures. As drug development progresses, these quantities increase dramatically. Safety management of toxic molecules is just one of the potential complexities. The incorporation of polyethylene glycol (PEG) or polysarcosine into linkers means laboratories no longer work with crystalline molecules, complicating purification of the payload-linker system. To overcome this challenge, companies must employ chromatographic methods—a step that introduces new difficulties: even for the payload-linker system alone, multiple chromatographic separations are required to maintain purity.

How can we improve the ADC?

Although the development process of ADCs is highly complex, several emerging approaches hold promise for significantly streamlining this workflow. Traditional ADCs still have considerable room for improvement in optimizing their therapeutic efficacy, with linker technology emerging as one of the most promising avenues in this field. GlycoConnect? developed by Synaffix, a subsidiary of Lonza, alters the binding mechanism between linkers and antibodies by enzymatically modifying the natural glycan chains of antibodies to facilitate conjugation. Another technology, HydraSpace?, introduces hydrophilic linker components to enhance safety, stability, and conjugation convenience while mitigating hydrophobic effects. These innovations are expected to improve solubility, reduce aggregation, and optimize pharmacokinetic properties.

Artificial intelligence (AI) has emerged as another pivotal force in ADC development. By enabling comprehensive testing of potential conjugates through computer simulations, it significantly reduces the trial-and-error phases downstream that often hinder R&D progress and drive up costs. Furthermore, AI-powered pathway exploration is helping manufacturers optimize development workflows by integrating synthesis and supply chain data to identify the most cost-effective approaches. AI is increasingly dominating the ADC field, being applied in antibody engineering design and optimizing payload-linker properties. While it cannot replace a deep understanding of chemical principles or the various challenges inherent in development, it holds tremendous potential to accelerate this process.

Although ADCs are highly complex pharmaceutical compounds, many associated development risks are foreseeable—provided that ADC developers clearly understand their priorities. In certain cases, they may focus primarily on biological aspects, such as developing antibodies capable of targeting specific targets, while lacking expertise in chemistry, which plays a critical role in linker design, purification, and large-scale production.

brief summary ：

The linker plays a pivotal role in the design and application of antibody-drug conjugates (ADCs), serving as a bridge between antibodies and cytotoxic drugs while significantly influencing the stability of ADC systems and the payload release profile. It is a critical component that determines both the toxicity and clinical efficacy of ADC therapies. Tek Biotechnology (Tianjin) Co., Ltd. has established a comprehensive ADC development platform utilizing phage display technology and yeast display technology, providing clients with high-quality, one-stop services for ADC development and drug-likeness assessment. With extensive expertise in ADC conjugation, Tek Biotechnology offers diverse linker design options—including cleavable and non-cleavable linkers—as well as customized conjugation strategies (including site-specific conjugation, non-site-specific conjugation, and tailored modification approaches) to meet diverse research requirements.

References ：

[1] Lundahl, M.L.E., Fogli, S., Colavita, P.E. & Scanlan, E.M. RSC Chem Biol. 2, 1004-1020 (2021).

[2] Christoforou, I., et al. Nanomaterials (Basel) 15, 1762 (2025).

[3] Verkade, J.M.M., et al. Antibodies (Basel) 7, 12 (2018).

[4] Huang, L., Qin, G., Gong, C. Huang, L., Qin, G., Gong, C. et al. Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting ADCs. Nat Commun 16, 9687 (2025).

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