The unique properties of polyethylene glycol (PEG) make it an ideal linker material and are widely used in the research and development and application of various ADCs. PEG linkers can not only improve the water solubility and stability of ADC, but also prolong its half-life and reduce immunogenicity, thereby improving the pharmacokinetic properties and safety of drugs. In the future, the design and optimization of PEG linkers will further promote the development of ADC therapy and provide more effective options for the treatment of cancer and other diseases.

Antibody Drug Conjugate

Antibody-Drug Conjugate (ADC) is an innovative biologic that combines the targeting properties of monoclonal antibodies with the therapeutic effects of cytotoxic drugs. The basic components of ADCs include three parts: specific antibodies, cytotoxic drugs, and linkers. Specific antibodies can recognize and bind to specific antigens on the surface of tumor cells, allowing ADCs to accurately locate target cells. Linkers are used to stably connect antibodies and cytotoxic drugs together to ensure that the drugs remain inactive before entering the cells. Once ADC binds to tumor cells, enzymes in the cells hydrolyze the linkers, releasing cytotoxic drugs, which in turn trigger cell apoptosis. Compared with traditional chemotherapy, the targeting of ADCs enables them to more effectively eliminate cancer cells without affecting normal cells, thereby significantly reducing adverse reactions and improving the quality of life of patients.

Fig. 1. ADC structure (Drug Discovery Today: Technologies. 2018, 30: 71-83).

In recent years, ADC has achieved remarkable success in the treatment of various cancers such as breast cancer, lymphoma and lung cancer. For example, trastuzumab emtansine (Kadcyla) is an ADC for HER2-positive breast cancer, which effectively treats this incurable cancer by targeting HER2 antigen to release cytotoxic drugs. In addition, the flexibility of ADC also enables it to be used in combination with other treatments (such as immunotherapy or radiotherapy) to enhance the overall efficacy. Despite the great potential of ADC, there are still some challenges, such as drug resistance, drug stability, and production costs. Therefore, researchers are working to optimize the design of linkers, improve the selectivity of cytotoxic drugs, and improve the preparation process of ADC to promote the development of ADC in clinical applications.

ADC Linker Chemistry

ADC linkers are one of the core components of ADCs and play a key role in connecting monoclonal antibodies to cytotoxic drugs. The design of linkers is crucial, as it directly affects the drug stability, targeting, and therapeutic effects of ADCs. The main function of linkers is to maintain the stability between antibodies and cytotoxic drugs in the body, preventing the release of drugs before entering target cells, thereby avoiding damage to healthy cells. At the same time, linkers must effectively release cytotoxic drugs at the appropriate time and location (i.e., inside target cells). This selective release is usually triggered by specific enzymes or environmental factors (such as acidic environments) in tumor cells, so the selection and design of linkers must be very precise.

According to their stability and release mechanism, ADC linkers are generally divided into two categories: cleavable linkers and non-cleavable linkers. According to the type of linker, it can be divided into PEG linkers, peptide linkers, disulfide linkers, acid-sensitive linkers, etc. Among them, PEG linker and peptide linker are both common linker types.

What is Polyethylene Glycol?

Polyethylene Glycol is a polyether compound widely used in several pharmaceutical, industrial, and biological applications. It is derived from ethylene glycol, synthesized through a polymerization process, and is available in various molecular weights that dictate its specific usage. PEG is highly soluble in water and many organic solvents, making it a versatile compound across different fields. In pharmaceuticals, PEG is often employed as an excipient or a delivery vehicle. Its ability to link with various active ingredients enhances the stability and solubility of drugs, thus improving bioavailability. It is also used in the formulation of laxatives, serving as an osmotic agent that helps in bowel movements.

Fig. 2. PEG structure.

One of the most notable applications of PEG is in the field of bioconjugation, where it serves as a PEGylation agent. PEGylation involves the attachment of PEG chains to molecules like antibody, proteins, peptides, or small drug molecules. This process significantly enhances the therapeutic efficacy of drugs by increasing their solubility, reducing immunogenicity, and extending their half-life in circulation. PEG linkers are widely used in the development of PEGylated pharmaceuticals, which are effective in treating diseases such as cancer, hepatitis, and multiple sclerosis.

What are PEG Linkers?

PEG linker is a molecular bridge built on the basis of PEG, which is usually used to connect drug molecules, antibodies, proteins or other bioactive substances to targeting carriers. The core of PEG linker is its flexibility and chemical inertness, making it a common biopharmaceutical linker, especially widely used in complex drug systems such as ADCs. PEG linker has many advantages, the first of which is to enhance water solubility. Many small molecule drugs or proteins have poor water solubility in the body. The introduction of PEG linker can greatly improve the water solubility of the drug, thereby improving the bioavailability of the drug. Secondly, the PEG linker can prolong the half-life of the drug, and form a protective barrier outside the drug molecule to reduce its rate of enzymatic degradation or clearance, thereby increasing the effective time of the drug in the body. Finally, PEG linkers can also provide controllable molecular spacing, which helps to precisely regulate the release and targeting of drugs.

PEG Linkers from BOC Sciences

Types of PEG Linker

• Linear PEG Linkers: These are the simplest form of PEG linkers, consisting of a single, unbranched chain of ethylene glycol units. They are often used for their ability to provide flexible, hydrophilic links between molecules. Linear PEG linkers are employed in drug delivery systems, where they enhance the solubility and circulation time of therapeutic molecules.
• Branched PEG Linkers: Unlike linear PEG linkers, branched PEG linkers have multiple arms extending from a central core. This branching can lead to higher molecular weights and increased functionality. Branched PEG linkers are used to create multivalent compounds and to improve the pharmacokinetics of drugs by reducing their renal clearance and immune recognition.
• Multi-Arm PEG Linkers: These are a more complex form of branched PEG linkers, with three or more arms. Multi-arm PEG linkers are used in the creation of hydrogels and other biomaterials. They provide multiple attachment points, which is useful in applications such as drug delivery, tissue engineering, and surface modification.
• Heterobifunctional PEG Linkers: These linkers have different functional groups at each end, allowing for the conjugation of two different molecules. This specificity is particularly useful in targeted drug delivery, where one end of the PEG linker can attach to a therapeutic agent and the other to a targeting molecule, such as an antibody or peptide.
• Homobifunctional PEG Linkers: These linkers have the same functional groups at both ends, enabling the conjugation of similar or identical molecules. They are often used in protein cross-linking, where they can help stabilize protein structures or create protein complexes.
• Cleavable PEG Linkers: Cleavable PEG linkers are designed to be broken down under specific conditions, releasing the attached molecules. This feature is beneficial in controlled drug delivery systems, where the drug is released only in the targeted environment, such as in response to a change in pH or the presence of specific enzymes.

Application of PEG Linkers

PEG linkers play a vital role in various biotechnological and pharmaceutical applications, primarily by enhancing the solubility, stability, and biocompatibility of therapeutic molecules. One of its most notable uses is in ADCs, where PEG linkers connect therapeutic agents and antibodies to facilitate targeted drug delivery. By optimizing the hydrophilicity of the conjugate, PEG linkers can reduce aggregation, extend circulation time, and minimize immune recognition, thereby improving pharmacokinetics. In addition, PEG linkers are used in peptide synthesis, protein modification, and nucleic acid delivery systems, where they act as flexible spacers that enhance molecular mobility and functional stability. Their ability to fine-tune drug release rates and improve biodistribution makes them a valuable tool in drug delivery systems that ensure more efficient and targeted therapeutic outcomes.

PEG Linker for ADC Drugs

A key example of PEG linkers in ADCs is their use in trastuzumab emtansine (T-DM1), an approved ADC used for treating HER2-positive breast cancer. In T-DM1, a stable, non-cleavable PEG-based linker is employed to attach the cytotoxic agent DM1, a potent microtubule inhibitor, to trastuzumab, an anti-HER2 monoclonal antibody. The PEG linker ensures that DM1 remains inactive until it reaches the cancer cell, where it is released upon internalization, leading to targeted cell death. Moreover, PEG linkers can be cleavable or non-cleavable, depending on the desired drug release mechanism. Cleavable PEG linkers are designed to release the cytotoxic drug once inside the cancer cell, typically triggered by environmental factors such as pH or enzymes. Non-cleavable linkers, like the one used in T-DM1, require complete internalization and degradation of the ADC before the drug is released.

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