Antibody-drug Conjugates (Adc): A Noval Chemotherapic Approach

Although there have been recent breakthroughs in immunotherapy and cell treatments, chemotherapy continues to be the primary approach in cancer treatment. Nevertheless, traditional chemotherapeutics, while exhibiting strong cytotoxicity against cancerous cells, frequently have a low therapeutic index and can cause toxicity on healthy tissues, so greatly reducing their clinical effectiveness. Therefore, the development of drug delivery systems that have a high level of effectiveness and minimal toxicity to the body could be a successful approach to addressing the issue of treating malignancies. Therefore, a new and innovative idea, known as antibody‒drug conjugates (ADCs), has been created and advanced. An ADC is usually produced by using an antibody that specifically targets an antigen found on tumors or a closely comparable antigen. The antibody is then linked to several payloads using suitable linkers. An antibody-drug conjugate (ADC) synergistically combines the precise targeting skills of a monoclonal antibody (mAb) with the potent therapeutic effects of the drug payloads specifically in malignant tissues. adc payload have experienced rapid growth as a pharmacological category in the field of oncology due to their reduced adverse effects, wider range of therapy possibilities, and increased therapeutic index.

Background:

The notion of ADC medicines was initially introduced in 19136 by German Nobel Laureate Paul Ehrlich. However, it was not until 1975 when the utilization of hybridoma technology for the production of monoclonal antibodies truly initiated the age of producing ADC medicines. ADC medicines have experienced three generations of advancement, propelled by progressively advanced technologies. The initial generation of ADC medicines utilized conventional chemotherapeutics including methotrexate,  doxorubicin and vinblastine as cytotoxic payloads. Nevertheless, due to their inadequate ability to kill cancer cells, lack of specificity for tumors, and limited aggregation in the targeted cells, these initial-generation ADCs demonstrated even lower effectiveness than the original drugs they were derived from, leading to their failure in clinical trials.

Current Scenario regarding ADC:

Despite the advancement of ADCs through three generations, the present payloads continue to exhibit clinical constraints, including significant side effects and the emergence of drug resistance. There remains a significant demand in the medical field to create more powerful ADC payloads, preferably with improved therapeutic indices. Furthermore, there are ongoing efforts to develop new ADC payloads such as carmaphycins, RNA inhibitors, NAMPT inhibitors, and Bcl-xL inhibitors. However, the utilization of immunomodulators as payloads in immune ADCs has garnered considerable interest due to their crucial functions in tumor immunotherapy. Instead of utilizing individual basic molecules as their payloads, a number of innovative approaches for creating ADCs with more intricate payloads have arisen. For instance, ADC payloads including photosensitizers or PROTACs have been utilized. Additionally, techniques have been devised to combine many payloads, each with distinct targets, into an individual antibody. These innovative tactics have the potential to pave the way for the development of the next wave of ADCs.

Bottom Line:

Tubulin inhibitors and DNA destructive compounds are frequently used as payloads in ADCs, with tubulin inhibitors representing over 50% of the ADC medicines currently being developed for clinical use. Nevertheless, because of the constraints in the clinical application of conventional ADC payloads, including insufficient effectiveness and the emergence of developed drug resistance, researchers are currently working on creating new and highly effective ADC payloads that target a variety of different molecules and have fewer adverse effects.