Explosion of Antibody Drug Conjugates in Cancer

By Alexander An on September 18th, 2023

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Image from  https://www.cshl.edu/can-our-own-immune-system-fight-off-cancer/

 

Since the approval of Mylotarg in 2000, there have been only 13 antibody-drug conjugates (ADCs) approved worldwide on the market, with over 100 ADCs in clinical trials. Among these, 6 are used in hematological malignancies (targeting antigens such as CD33, CD30, CD22, CD79b, BCMA, and CD19), while 7 are employed in solid tumors (targeting antigens including HER2, nectin-4, TROP2, tissue factor, and folate receptor alpha (FRα)). ADCs are agents made up of monoclonal antibodies linked to potent payloads, allowing for selective targeting of cancer cells. This targeting of specific antigens expressed on the surface of cancer cells enhance selectivity, reduces the minimum effective dose, increases the delivery of powerful cytotoxic payloads, and diminishes the off-target adverse impacts associated with chemotherapy. The main components of ADCs include the target antigen, antibody, linker, and payload.

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List of approved ADCs from https://www.nature.com/articles/s41573-023-00709-2 (Blenrep was withdrawn from the market in 2022)

The most effective ADCs are those that can successfully transport the payload to the target spot without endangering the neighboring healthy cells. The appropriate antigen, antibody, and linker must be chosen for this purpose. The required target antigen density needed is 10,000 copies/cell or greater to trigger efficient receptor-mediated endocytosis. Additionally, the surface of cancerous cells should overexpress the target antigen compared to healthy cells. A prime example would be the target antigen for triple-positive breast cancer, human epidermal growth factor receptor 2 (HER2), which is expressed 100 times higher in cancer cells than in healthy cells. For easy access for ADCs, the target antigen must also be exposed on the cancer cell's surface, facing outward. Finally, to prevent the activity of ADCs outside of the tumor site, the antigen should not be secreted into the systemic circulation.

 

 

 

 

 

 

 

 

 

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Image of key components of an ADC from https://www.sciencedirect.com/science/article/pii/S0753332223001968?via%3Dihub

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The antibody should have a high affinity for the target antigen, be minimally immunogenic, have an extended plasma half-life, and internalize quickly. The human body has a total of five antibodies, with immunoglobulin G (IgG) accounting for 70% to 85% of the total antibodies and having a half-life of 21 days. IgG is most frequently employed in the creation of ADCs because it is ubiquitous and has a high starting potency for immunological effectors. When compared to other subclasses, IgG1 is the most often employed antibody in the production of ADCs because it is most efficient in inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). IgG has a high molecular weight, making it challenging to enter the blood vessels and reach the intended tumor site. Due to this, researchers are using low molecular weight antibodies in the development of ADCs.

 

The linker that joins the antibody with the payload is another crucial part of ADCs. The linker is responsible for the way the payload is released to the target site via protonolysis, thiol reduction, proteolysis, or carbohydrate hydrolysis. Linker length, conjugation site, and steric hindrance are three key variables that determine linker stability and payload release. High water solubility, no aggregation formation, and no premature payload release would characterize the perfect linker. Since it ties up the payload closer to the steric shield of the antibody, a short linker is ideal for the stability of an ADC. The type of conjugation/linkage methods utilized to join payload and monoclonal antibodies determines how quickly the payload is released as well. When compared to ADCs with disulfide links, ADCs with maleimide links release their payload more quickly. The pace of payload release is greatly influenced by the conjugation site. Steric hindrance at the conjugation site increases ADCs' stability but decreases payload release speed.

 

Microtubule inhibitors, DNA-damaging compounds, and topoisomerase I inhibitors are the three main types of payloads. Low-potency payloads were initially used but were discontinued due to poor clinical activity. ADCs are currently being developed with increasingly potent cytotoxic payloads, including microtubule inhibitors like monomethyl auristatin E and DNA-damaging compounds like pyrrolobenzodiazepines and calicheamicin. However, the use of highly effective payloads has limited the biological dosages that can be administered, often resulting in inadequate payload distribution to tumors with lower target antigen concentrations. The quantity of payload molecules per ADC, the prevalence of multi-drug resistance efflux pumps in tumors, the potential for bystander functionality of the payload once released, and payload clearance are additional parameters that may affect the payload's effectiveness.

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ADCs in clinical trials classified by payload class from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10464553/

 

When it comes to creating the best ADCs, there are many difficulties. ADCs, or antibody-drug conjugate agents, have been terminated for a variety of reasons, including unacceptable toxicity and a lack of antitumor effects at the maximum tolerated dose. Due to the complex pharmacokinetic (PK) profile of an ADC, limitations include the creation of a pharmacokinetic-pharmacodynamic model for clinical usage. Second, due to the high molecular weight of ADCs, it may be challenging for them to penetrate solid tumors. Only a limited portion of the cytotoxic payloads, nevertheless, actually reach the tumor site. Factors such as tumor cells developing new blood vessels and developing drug resistance further complicate the ability of ADCs to reach the tumor. Finally, early release of the payload into the systemic circulation can result in off-target effects such as thrombocytopenia, anemia, neutropenia, leukopenia, and hepatotoxicity.

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Promising targets are the subject of increasing investigation. The cell-surface adhesion molecule CEACAM5, which serves as a tumor target and a diagnostic marker, is one such target. Patients with non-small-cell lung, breast, and pancreatic cancer are undergoing treatment with tusamitamab ravtansine/SAR408701 in clinical studies. Additionally, patients with metastatic colorectal cancer who have undergone extensive prior therapies have shown therapeutic effectiveness with labetuzumab govitecan. HER3, which promotes cell proliferation by forming heteromers with other EGFR family members, represents another target. An example includes the patritumab deruxtecan in advanced breast cancer trial. ADCs may also find applications beyond cancer, including autoimmune and cardiovascular diseases. With various payload classes, linkers, and cancer targets under study, the future of ADCs appears promising.

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Check out my personal blog page as well here: https://medium.com/@alexanderan 

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