The field of antibody-drug conjugates (ADCs) has witnessed remarkable growth in recent years, offering a promising approach for targeted cancer therapy. ADCs combine the specificity of monoclonal antibodies with the potent cytotoxicity of small molecule drugs, enabling precise delivery of therapeutic agents to cancer cells while minimizing systemic toxicity. Peptide linkers play a crucial role in ADC design, as they connect the antibody to the payload and influence the pharmacokinetics, stability, and efficacy of the conjugate. One key factor that can significantly impact ADC properties is the charge of the peptide linker. In this blog post, we will explore the influence of peptide linker charge on ADC properties and discuss how our company, a leading supplier of peptide linkers for ADCs, can help researchers optimize their ADC designs.
Understanding Peptide Linkers in ADCs
Peptide linkers are short amino acid sequences that are used to connect the antibody and the cytotoxic payload in an ADC. They are designed to be stable in circulation but cleavable at the target site, allowing the release of the payload inside the cancer cells. The choice of peptide linker can have a profound impact on the performance of the ADC, as it affects the pharmacokinetics, stability, and efficacy of the conjugate.
There are several types of peptide linkers that are commonly used in ADCs, including cleavable and non-cleavable linkers. Cleavable linkers are designed to be cleaved by specific enzymes or under certain physiological conditions, such as low pH or high reducing potential, allowing the release of the payload inside the cancer cells. Non-cleavable linkers, on the other hand, remain intact throughout the circulation and are only released when the antibody is internalized and degraded by the cancer cells.
Influence of Peptide Linker Charge on ADC Properties
The charge of the peptide linker can have a significant impact on the properties of the ADC, including its solubility, stability, pharmacokinetics, and efficacy. Here are some of the key ways in which peptide linker charge can influence ADC properties:
Solubility
The charge of the peptide linker can affect the solubility of the ADC in aqueous solutions. Positively charged linkers can increase the solubility of the ADC by interacting with negatively charged molecules in the solution, while negatively charged linkers can decrease the solubility of the ADC by interacting with positively charged molecules. This can have important implications for the formulation and delivery of the ADC, as poor solubility can lead to aggregation, precipitation, and reduced bioavailability.
Stability
The charge of the peptide linker can also affect the stability of the ADC in circulation. Positively charged linkers can increase the stability of the ADC by interacting with negatively charged molecules in the blood, such as albumin and other plasma proteins, which can protect the ADC from degradation and clearance. Negatively charged linkers, on the other hand, can decrease the stability of the ADC by interacting with positively charged molecules in the blood, such as calcium ions and other cations, which can lead to aggregation and precipitation.
Pharmacokinetics
The charge of the peptide linker can also affect the pharmacokinetics of the ADC, including its half-life, clearance, and tissue distribution. Positively charged linkers can increase the half-life of the ADC by reducing its clearance from the circulation, while negatively charged linkers can decrease the half-life of the ADC by increasing its clearance from the circulation. This can have important implications for the dosing and scheduling of the ADC, as well as its efficacy and safety.
Efficacy
The charge of the peptide linker can also affect the efficacy of the ADC, including its ability to target cancer cells and deliver the payload. Positively charged linkers can increase the efficacy of the ADC by enhancing its binding to negatively charged cancer cells, while negatively charged linkers can decrease the efficacy of the ADC by reducing its binding to positively charged cancer cells. This can have important implications for the selection of the peptide linker and the design of the ADC, as well as its clinical performance.
Examples of Peptide Linkers with Different Charges
To illustrate the influence of peptide linker charge on ADC properties, let's take a look at some examples of peptide linkers with different charges:
Positively Charged Linkers
One example of a positively charged peptide linker is Alkyne-Val-Cit-PAB-OH. This linker contains a positively charged alkyne group, which can increase the solubility and stability of the ADC in aqueous solutions. It also contains a cleavable Val-Cit-PAB spacer, which can be cleaved by cathepsin B, a protease that is overexpressed in many cancer cells, allowing the release of the payload inside the cancer cells.
Negatively Charged Linkers
One example of a negatively charged peptide linker is DBCO-PEG4-Acid. This linker contains a negatively charged acid group, which can decrease the solubility and stability of the ADC in aqueous solutions. It also contains a non-cleavable DBCO-PEG4 spacer, which can remain intact throughout the circulation and is only released when the antibody is internalized and degraded by the cancer cells.
Neutral Linkers
One example of a neutral peptide linker is Acetylene-linker-Val-Cit-PABC-MMAE. This linker contains a neutral acetylene group, which can have a minimal impact on the solubility and stability of the ADC in aqueous solutions. It also contains a cleavable Val-Cit-PABC spacer, which can be cleaved by cathepsin B, allowing the release of the payload inside the cancer cells.
How Our Company Can Help
As a leading supplier of peptide linkers for ADCs, our company offers a wide range of peptide linkers with different charges, lengths, and structures to meet the diverse needs of researchers. Our peptide linkers are synthesized using high-quality materials and state-of-the-art techniques, ensuring their purity, stability, and reproducibility. We also offer custom synthesis services to help researchers design and synthesize peptide linkers that are tailored to their specific requirements.
In addition to our peptide linkers, we also offer a range of other products and services to support ADC research, including antibodies, payloads, conjugation reagents, and analytical services. Our team of experienced scientists and technical support staff is available to provide expert advice and assistance to help researchers optimize their ADC designs and achieve their research goals.
If you are interested in learning more about our peptide linkers for ADCs or our other products and services, please contact us to schedule a consultation. We look forward to working with you to advance the field of ADC research and develop innovative therapies for cancer and other diseases.
References
- Ducry, L., & Stump, B. (2010). Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. Bioconjugate Chemistry, 21(1), 5-13.
- Beck, A., Goetsch, L., Dumontet, C., & Corvaia, N. (2017). Strategies and challenges for the next generation of antibody-drug conjugates. Nature Reviews Drug Discovery, 16(5), 315-337.
- Junutula, J. R., Raab, H., Clark, S., Bhakta, S., Leipold, D. D., Weir, S., ... & Torgov, M. Y. (2008). CD30-targeted delivery of monomethyl auristatin E by the antibody-drug conjugate SGN-35 provides a therapeutic benefit in preclinical models of Hodgkin lymphoma. Blood, 111(5), 2721-2732.