In the development of antibody drug conjugates (ADCs), the design of linkers is of the same essential importance as that of monoclonal antibodies and cytotoxic drugs, because the linker impacts the efficacy and tolerability of ADCs. Now, Creative Biolabs has developed several strategies to generate suitable linkers for the conjugation of different antibodies and drugs.
To generate suitable linkers in ADC development is one of the biggest challenges. The linker needs to be exceedingly stable in systemic circulation before reaching the target but allows for rapid and efficient release from the cytotoxic compound in an active form at the target site. According to the different mechanisms of drug release, linkers in ADC development can be classified into two categories: cleavable linkers and noncleavable linkers. Cleavable linkers rely on the physiological stimuli, which mainly include chemically cleavable linkers and enzymatically cleavable linkers. Chemically cleavable linkers including acid-labile linkers and disulfide linkers are popular in the ADC clinical pipeline. For acid-labile linkers, intracellular release of payloads relies on the different pH between endosomes/lysosomes and blood. The release of disulﬁde-linked drugs is controlled by the factors in intracellular environment. Enzymatically cleavable linkers, peptide linkers and β-glucuronide linkers, are sensitive to enzymes located in cytoplasm. Alternatively, noncleavable linkers require proteolytic degradation. They depend on the internalization more than cleavable linkers do. In ADC development, several noncleavable alkyl and polymeric linkers have been explored. Different linkers have their advantages and limitations. Ultimately, the choice of the linker is unique tailored to the correlate antibody, drug and the disease to be treated. Based on the fully understanding of every client’s requirements, scientists from Creative Biolabs will select the most appropriate linkers for your ADC investigation.
It can be challenging that conjugation of the linker to the antibody at large scale without affecting the structure of the antibody, since proteins are very sensitive to changes in the environment, and changes in the structure of the antibody can affect the performance of the ADC in terms of both efficacy and safety. Because the linker serves as the interface between chemistry and biology, there is always the opportunity for unexpected reactivity during scale up of the conjugation process. Reactivity can be affected by many factors, just as with the scale-up of any process. With most advanced experience, Creative Biolabs has established fairly standard methods used in the production of ADCs, and developed robust, scalable, lab-scale conjugation processes that can be scaled up to provide the desired product consistently from batch-to-batch. After that, we have been able to transform lab-scale into large-scale production of this ADC with consistently high quality. In addition, we can now apply the experience gained in the scale-up of other ADCs to the production in our pipeline according to the most scientific progress and every custom’s interest.
We are offering different strategies of linkers in ADC development:
Jan Anderl, et al. Methods for Conjugating Antibodies to Nanocarriers. Antibody-Drug Conjugates, 2013:249-266.
Birte Nolting. Linker technologies for antibody-drug conjugates. Methods Mol Biol. 2013; 1045:71-100.
Cynthia A. Challener. Advances in Linker Technology: Improving the Safety and Efficacy of Antibody Drug Conjugates. BioPharm International. 2014; 27 (3).