Why do antibody drug conjugates hold such promise for the future of cancer treatment?

What are antibody-drug conjugates?

Antibody-drug conjugates (ADCs) are a targeted therapy used in cancer treatment, comprising an antibody, a cytotoxic drug, and a linker molecule. The antibody component specifically recognizes cancer cells by binding to their surface antigens, delivering the cytotoxic drug directly to the cancer cells while minimizing harm to healthy cells.. ADCs offer benefits such as improved outcomes, reduced side effects, resistance overcoming potential, and targeted drug delivery.

Antibody-drug conjugates (ADCs) embody an elegant mechanism that combines the power of antibodies and cytotoxic drugs to target and combat cancer cells. Through their three essential components, ADCs pave the way for a more precise and effective approach to cancer treatment.

How do ADCs work with regards to treating cancer?

1^st step: ADC attaches to the cancer cell’s surface

First, ADCs utilize monoclonal antibodies specifically designed to recognize and bind to unique antigens present on the surface of cancer cells. This targeted recognition allows for the selective delivery of the therapeutic payload to cancer cells, sparing healthy cells from unnecessary damage. Each ADC is tailored to match the antigen profile of the specific cancer type being treated, such as the notable targeting of HER2 in HER2-positive breast cancer.

2^nd step: ADC is internalized into the cancer cell

Once the ADC attaches to the cancer cell’s surface, the ADC is internalized into the cancer cell, propelled by receptor-mediated endocytosis. The complex formed by the antibody and antigen embarks on a journey to intracellular compartments like endosomes and lysosomes, laying the groundwork for the subsequent steps.

3^rd step: Release of the drug within the cancer cell

Within these intracellular compartments, a critical process takes place. The linker molecule, acting as the bridge between the antibody and the cytotoxic drug, undergoes enzymatic or chemical cleavage. This precise cleavage, triggered by factors specific to the intracellular environment, liberates the cytotoxic drug from its antibody carrier. The clever design of the linker ensures the drug’s controlled release within the cancer cell, safeguarding healthy tissues from unnecessary exposure.

4^th step: The drug goes into action leading to cancer cell death

Once released, the cytotoxic drug springs into action with remarkable potency. It disrupts crucial cellular processes, such as DNA replication or microtubule assembly, impeding the cancer cell’s ability to divide and grow. Even at low concentrations, the cytotoxic drug proves highly effective, driving cancer cell death and promoting therapeutic outcomes.

The intricate dance of the antibody, linker, and cytotoxic drug in ADCs represents a breakthrough in cancer therapy. By harnessing the targeting capabilities of antibodies, ADCs offer a tailored approach that delivers potent drugs directly to cancer cells while sparing healthy cells. This precise targeting seeks to maximize treatment efficacy while minimizing the side effects associated with traditional chemotherapy.

Antibody-drug conjugates still face several challenges when used to treat cancer

One challenge is the potential development of resistance. Cancer cells may acquire mechanisms to evade or eliminate ADCs, diminishing their effectiveness over time. Additionally, the heterogeneity of tumors, where different cancer cells express varying levels of antigens, can limit the efficacy of ADCs that target specific antigens.

Safety concerns also arise due to the cytotoxic nature of the drug component. Imperfect selectivity may result in off-target effects, where healthy cells are affected, leading to adverse reactions. Furthermore, the drug’s toxicity may impose limitations on the maximum dose that can be administered, potentially impacting the treatment’s efficacy on a local level.

Examples of key antibody drug conjugates used in cancer treatment

• Ado-trastuzumab emtansine (Kadcyla), Brentuximab vedotin (Adcetris), Polatuzumab vedotin (Polivy), and Trastuzumab deruxtecan (Enhertu) are important examples of antibody-drug conjugates (ADCs) making a significant impact in cancer therapy.
• Kadcyla, developed by Genentech/Roche, targets HER2 and has proven efficacy in treating HER2-positive breast cancer. By precisely targeting HER2, Kadcyla offers a targeted therapeutic approach tailored to this specific subtype of breast cancer, enhancing treatment outcomes and improving the lives of patients.
• Seattle Genetics/Seagen brings forth Adcetris, an ADC that targets CD30. Adcetris has demonstrated efficacy in Hodgkin lymphoma, systemic anaplastic large cell lymphoma, and other CD30-positive lymphomas. Its remarkable success in these indications has brought hope to patients with these challenging diseases.
• Genentech/Roche’s Polivy is designed to target CD79b, providing a promising treatment option for patients with diffuse large B-cell lymphoma. By specifically binding to CD79b, Polivy delivers its cytotoxic payload directly to the cancer cells, aiming to halt the progression of the disease and improve patient outcomes.
• Daiichi Sankyo and AstraZeneca have collaborated to develop Enhertu, an ADC targeting HER2. Enhertu has shown impressive efficacy in both HER2-positive breast cancer and HER2-positive gastric cancer. By effectively targeting HER2, Enhertu delivers a potent cytotoxic drug directly to cancer cells, offering new hope to patients battling these types of cancer.

To summarize, the field of antibody-drug conjugates (ADCs) is characterized by its dynamic nature. Despite initial setbacks and challenges, the number of approved ADCs and those undergoing clinical trials continues to rise steadily. This growth trajectory is expected to accelerate significantly in the coming decade. At Alcimed, we‘ll you updated on the latest developments in this exciting field. Should you have any project in this area, don’t hesitate to contact our team!

About the author, 

Volker Bischoff, Great Explorer Oncology, in Alcimed’s Healthcare team in Germany