Antibody-drug conjugates or ADCs are an important class of highly potent biopharmaceutical drugs designed as a targeted therapy for the treatment of people with cancer. As the hottest research topic, ADC technology is intended to target and kill only the cancer cells and spare healthy cells. ADCs are complex molecules composed of an antibody linked to a biologically active cytotoxic (anticancer) payload or drug. Antibody-drug conjugates are examples of bioconjugates and immunoconjugates.
A stable link between the antibody and the cytotoxic (anti-cancer) agent is a crucial aspect of an ADC conjugation. A highly stable ADC linker will ensure that less of the cytotoxic payload falls off in circulation, driving an improved safety profile, and will also ensure that more of the payload arrives at the cancer cell, driving enhanced efficacy. Linkers are based on chemical motifs including disulfides, hydrazones or peptides (cleavable), or thioethers (noncleavable) and control the distribution and delivery of the cytotoxic agent to the target cell. AxisPharm provides the most comprehensive linker and payloads for conjugation research.
AxisPharm develops a broad range of Linkers and provides custom linker synthesis. Our current product catalog covers click chemistry tools such as DBCO, Tetrazine, TCO, BCN, and Cyclopropane, etc., biotin linkers, PEG linkers, peptide linkers, glucuronide linkers, photo cleavable linkers, Fluorescent Dye probe linkers and folic acid peg linkers.
Carboxyl and Active ester Reactive
Copper Free Click Chemistry
Fluorescent PEG Labeling
Lipid PEG in Drug Delivery
Metal Surface Binding
Polyethylene glycol (PEG) linkers in Antibody Drug Conjugation
Polyethylene glycol (PEG) linkers are commonly used in antibody drug conjugates (ADCs) to attach cytotoxic drugs to antibodies. PEG linkers play a crucial role in ADCs by providing stability, control over drug release, and reducing immunogenicity.
Attachment to the antibody: Polyethylene Glycol PEG linkers are often used to attach the cytotoxic drug to the antibody. The PEG linker is designed to have a reactive group at one end that can be covalently conjugated to a specific site on the antibody, such as cysteine residues or engineered amino acids.
Spacer effect: Polyethylene Glycol PEG linkers act as spacers between the antibody and the cytotoxic drug. The length and flexibility of the PEG chain can influence the binding affinity of the antibody and the pharmacokinetic properties of the ADC antibody drug conjugate. By varying the length and structure of the PEG linker, the drug-antibody ratio (DAR) and properties of the ADC can be optimized and fine-tuned.
Stability and solubility: Polyethylene Glycol PEG linkers enhance the stability and solubility of ADCs. The hydrophilic nature of PEG helps to increase the solubility of the conjugate in aqueous solutions, reduce protein aggregation and improve ADC antibody drug conjugate bioavailability. PEG may also provide a protective barrier around the cytotoxic drug, preventing it from degradation and minimizing premature drug release, therefore, reduce the off-target toxicity.
Controlled drug release: Polyethylene Glycol PEG linkers can be designed to be stable in circulation but susceptible to cleavage in the target tumor environment, such as in the presence of specific enzymes or low pH conditions. This controlled release mechanism ensures that the cytotoxic drug is delivered selectively to the tumor cells, minimizing off-target toxicity and improving therapeutic efficacy.
Reduced immunogenicity: PEGylation of the ADC antibody drug conjugate can help reduce immunogenicity, which is the immune response generated against foreign substances. The PEG moiety can shield the antibody and the drug from the immune system, decreasing the likelihood of an immune response against the conjugate.
Antibody Drug Conjugate Examples
One example of the application of Polyethylene Glycol (PEG) linkers in antibody drug conjugation is the ADC called Ado-trastuzumab emtansine (Kadcyla®), an FDA-approved ADC. Ado-trastuzumab emtansine is used for the treatment of HER2-positive breast cancer. It consists of the monoclonal antibody trastuzumab, which specifically targets the HER2 receptor overexpressed on cancer cells, the cytotoxic drug DM1 (emtansine), and the PEG linker that conjugate DM1 to trastuzumab.
The PEG linker in Ado-trastuzumab emtansine serves several important functions. Firstly, it helps maintain the stability of the ADC by preventing premature release or degradation of the cytotoxic drug during circulation. The PEG linker shields DM1 from proteolytic enzymes and provides protection against clearance mechanisms in the body.
Secondly, the PEG linker acts as a spacer between the antibody and the cytotoxic drug, allowing for flexibility and optimal positioning of the drug in relation to the target receptor. This spatial arrangement helps to maximize the binding of the ADC to the HER2 receptor on cancer cells, enhancing its specificity and therapeutic efficacy.
Additionally, the PEG linker in Ado-trastuzumab emtansine contributes to the pharmacokinetic properties of the ADC. The hydrophilic nature of PEG improves the solubility of the conjugate in aqueous solutions, facilitating its administration and distribution in the body.
Lastly, the PEGylation of Ado-trastuzumab emtansine helps reduce immunogenicity. The PEG moiety acts as a shield, reducing the likelihood of an immune response against the ADC, thus minimizing the risk of adverse reactions.
The crucial role of the PEG linker in Ado-trastuzumab emtansine in maintaining stability, optimizing drug positioning, improving solubility, and reducing immunogenicity greatly exemplifies the successful application of PEG linkers in antibody drug conjugation for targeted cancer therapy.
ADC Antibody Drug Conjugation Manufacturing
AxisPharm is a global leading ADC antibody drug conjugation manufacturing ADC linker supplier and bioconjugation service provider. The company has over 5000 functional ADC linkers in stock for express delivery. Our custom synthesis and manufacturing services for PEG linkers, bioconjugates, and fluorescent probes offer tailored ADC linkers to meet our clients’ specified requirements, including adjusting the length, functional groups, cleavability, or other properties.
AxisPharm adheres to high-quality standards and regulatory guidelines in our manufacturing processes and ensures that the PEG linkers produced meet the required specifications and are suitable for use in pharmaceutical applications.
We conduct QC with the highest possible standard using our state of art analytical instruments and well-established protocols throughout the project. Our collaborative support provides expertise and guidance during the development, optimization, and scale-up stages of linker synthesis.
AxisPharm prioritizes client confidentiality and intellectual property protection. At AxisPharm, we handle our clients’ projects with discretion and maintain confidentiality.