ADC Conjugation – An Innovative Approach for Optimizing Targeted Delivery

Over the years, researchers and scientists have been on the lookout to find effective ways to treat various types of oncological disorders. This is because one of the approaches, such as chemotherapy, results in killing of both healthy and cancerous cells. Therefore, an innovative approach that can kill the targeted cell while minimizing toxicity was highly demanded over the years. As a result, innovators came up with the idea of magic bullets, antibody drug conjugates (ADCs). Linked to this is ADC Conjugation, which is a crucial step in the making of ADC

What is an ADC?

ADC is a versatile class of biotherapeutics that can deliver potent toxins directly to the tumor site. It is comprised of three components, namely antibody, drug and linker. The antibody is conjugated to the drug via a linker molecule.

Components of an ADC?

ADC Conjugates: Components of ADC

ADCs candidates that were produced in the beginning, had various limitations. These ADCs were not using humanized versions of antibodies, triggering several immune reactions. Moreover, the linkers used were not stable under different environmental conditions. Further, the drug / payloads used were also not enough cytotoxic to kill all the tumor cells.

ADC Linker and Conjugation Technologies

To overcome all these challenges, ADC linker and conjugation technologies were introduced. These technologies resolved the problems associated with ADCs to a greater extent. These technologies can be broadly categorized into three categories, namely, ADC conjugation technologies, ADC linker technologies and ADC linker-payload technologies.

ADC conjugation technologies were mainly focused on solving the very first issue with ADCs. The technology providers offering these types of technologies work on engineering / modifications of antibodies. The alterations in structure and design of antibody can greatly contribute to the tolerability of an ADCs in human body. It has been observed that humanized forms of antibody suppress immune reactions.

On the other hand, ADC linker technologies deal with concerns related to stability of linkers. These technologies are designed to improve stability of linkers in systemic circulation. It is important so that the payload doesn’t get cleaved before reaching the desired site. Further, ADC linker-payload technologies answers the very last limitation regarding ADCs. Some technology providers are engaged in the development of linker-payload technologies to improve the quality of payloads used. It is pivotal to ensure that the drug used is capable of degradation if released too early or leaks from the cancer cell. Therefore, these technologies enables the development of site-specific, stable and potent homogenous ADCs which can effectively enhance the therapeutic window.

ADC Conjugation Process

ADC Conjugates: Process

ADC is prepared by conjugating antibody with the cytotoxic payload along with the help of a linker. The conjugation process occurs through various modes of conjugation at different sites for the development of different novel targets with increased safety, efficacy and tolerability. Thereafter, the ADC interacts with the target cell and undergoes internalization eventually resulting in in the cell death. It is interesting to note that payloads are continuously evolving. The classical potent drugs killed tumor cells by inhibiting crucial cellular processes and by interfering with DNA. However, currently oligonucleotide-based conjugates are also employed which can kill tumor cells by inhibiting RNA transcription and translation.

Concluding Remarks

It is evident that the evolutionary advances in conjugation and linker technologies have enabled the development of viable treatment options. Such improvements have significantly altered the therapeutic potential and likely applications of ADCs. In other words, conjugated drugs, based on improved technologies are more selective in targeting diseased cells and have broader therapeutic windows. However, the choice of a suitable target antigen, cytotoxic payload, conjugation approach used, and linker chemistry involved, are equally crucial elements for manufacturing viable leads. In fact, linker instability and product heterogeneity are known to severely compromise ADC efficacy and therapeutic window, which may cause difficulties in the lead optimization for clinical application, eventually resulting in trial failure. As a result, there are a number of efforts directed towards the development of better / more stable linkers and site-specific conjugation methods that enable manufacturers to synthesize homogeneous batches of ADCs.

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