Reshaping Cancer Care Through ADC Drugs

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Regardless of current oncology developments, conventional anticancer treatments might have limitations. Decades of dedicated research are resulting in the capability to create a new generation of Antibody-drug conjugate or ADC.

Figure 1.0: Structure of an antibody-drug conjugate.
(Source: https://commons.wikimedia.org/wiki/File:Antibody-drug_conjugate_structure.svg)


What are Antibody Drug Conjugates?
An ADC is a unique combination of the targeted monoclonal antibodies, a stable chemical linker and a protein cytotoxic agent. Based on preclinical studies, the monoclonal Ab component of the ADC binds to the target antigen on tumor cell surface. Target Antigens are preferentially or exclusively expressed on the surface of cancer cells to provide a tumor specific binding site for the monoclonal Ab.
Monoclonal Ab have the ability to persist in circulation overtime allowing for prolonged exposure to the cancer cells and to become internalized by the cancer cell Stable linker attaches cytotoxic agents to monoclonal Abs and allows ADC to remain inactive during
circulation. Linker stability during circulation controls the delivery of the cytotoxic payload to the target cell. The use of more stable linkers may allow the delivery of cytotoxic agent to the cancer cell over an extended period of time.

Cytotoxic agents incorporated into ADC can be up to one thousand folds more potent than currently used drugs. ADCs have multipurpose mechanisms of action that represent the potential therapeutic approach. Monoclonal Antibody component may possess its own anticancer activities which may include prevention of signaling, Antibody-dependent cellular cytotoxicity (ADCC) and Induction of apoptosis.

Upon binding to the target antigen that is preferentially or exclusively expressed on the cancer cell, the ADC/Antigen complex may be internalized through a process known as Receptor-mediated endocytosis. Based on preclinical models internalization of the Antibody Drug Conjugate antigen complex is followed by lysosomal degradation of the complex resulting in release of the protein cytotoxic agent. The cytotoxic agent interacts with cellular machinery to elicit cell death.

Figure 2: Antibody Drug Conjugate

Commercially Available Antibody Drug Conjugates
The very first Antibody Drug Conjugate to acquire FDA approval was Pfizer’s Mylotarg. It’s the first ADC drug was discovered for CD33-positive acute myeloid leukemia (AML) patients in 2000. Owing to issues concerning the stability of the cleavable linker of Mylotarg led to its withdrawal from the market in 2010. Mylotarg was brought to market by the FDA in 2017 after lowering its dosage.

In 2011, Brentuximab vedotin (Adcetris) by Seattle Genetics Company gained approval by the US Food and Drug Administration (FDA). Adcetris is a CD30-specific antibody–drug conjugate to treat the patients with Hodgkin’s lymphoma and patients with systemic anaplastic large cell lymphoma (ALCL).


In the recent years, several new ADCs entered the market:
• Polatuzumab vedotin , Polivy, is an antibody-drug conjugate designed for the treatment of large B-cell lymphoma. Polivy was approved by FDA in June 2019. This drug was developed by Genentech and Roche Company.
• Padcev (enfortumab vedotin) was the first nectin-4-directed antibody-drug conjugate approved for the treatment of advanced urothelial cancer. This drug was developed by the company Astellas Pharma and Seattle Genetics in 2019.
• Another monoclonal antibody medication, Trastuzumab deruxtecan used for the treatment of breast cancer was approved by FDA in the year 2019.

ADCs are under investigation for many different cancer types. Moreover, there are several biopharma companies developing ADCs to treat all type of cancer.


Are there any Challenges which is hindering their wider development?
While ADCs signify a thrilling class of anticancer agents, there are several challenges that hinder their development.
• Stability of the drug
• Physical instabilities caused during manufacturing leads to aggregate formation and diminished drug activity.
• Sometimes, without efficient breakdown of cytotoxic agent the toxin can accumulate in the bloodstream, causing the side effects typically associated with systemic chemotherapy.
• Resistance is another major obstacle for ADCs. ADC-resistant cancer cells were reported which revealed over-expression of multi-drug efflux transporters.

The drug developers are overcoming these issues as demonstrated by the multiple recent FDA approvals and large investments in this category. Development of a comprehensive preclinical strategy addressing the mechanisms of action, efficacy, toxicity, and biomarker strategy might be a key component to defeating these challenges.

Conclusion
ADC research and development has escalated and developed throughout the year. With the approval of Adcetris and more than 200 ADCs currently undergoing human trials, ADCs are becoming a viable method for selectively delivering a highly cytotoxic agent to the tumor cells while sparing the normal tissue. Further research in ADCs will continue to produce highly selective and potent ADCs. In the era of personalized medicines, ADC treatment can be an excellent alternative over conventional chemotherapies.

References
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By – Ariba Khan

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