The cure for cancer has long been sought after by modern medicine. While traditional approaches to treating cancer have often produced unsuccessful results, antibody-drug conjugates promise to change that reality.
What are antibody-drug conjugates?
Antibody-drug conjugates (ADCs) are biopharmaceutical drug products. ADCs are bioconjugates that possess a complex chemical composition. The molecular structure of ADCs is composed of a stable covalent link between an antibody and a biologically active cytotoxic agent.
The attachment of molecules is known as conjugation. ADCs are an example of immunoconjugates, which are molecules that are created by an antibody being conjugated to a second molecule. The joint molecule in immunoconjugates tends to be a toxin, a radioisotope, or a label. In the case of ADCs, the adhered molecule is a cytotoxin.
What are antibody-drug conjugates used for?
Antibody-drug conjugates are used in the treatment of cancer. The composition of ADCs takes advantage of the targeting capabilities of monoclonal antibodies and the cancer-killing properties of cytotoxic drugs. ADCs can combat cancerous cells using an extremely precise form of chemotherapy that avoids killing healthy cells.
How does an antibody-drug conjugate work?
Antibodies in ADCs directly target antigens found in tumor cells and stick to them, creating a chemical reaction in the cell. This triggers a signal within the tumor cells, causing them to absorb the antibodies together with the cytotoxic agent. Once it is inside the cell, the cytotoxic agent kills the cancer.
Conjugates for cancer therapy can directly address a cancerous area thanks to the link between a cytotoxic agent and an antibody that targets antigens found in tumor cells. Pyrrolobenzodiazepines, for instance, can cause a reaction by binding in the minor groove of DNA, while causing minimal distortion to it. A direct approach to cancer therapy limits side effects and is safer than other chemotherapeutic methods.
Why are antibody-drug conjugates important?
Antibody-drug conjugates are important because they promise to forever change the way cancer therapy works. Because it can combat cancerous cells without harming healthy cells in the process, antibody-drug conjugation chemistry has the potential to replace chemotherapy as the main method to treat cancer.
The effectiveness of antibody-drug conjugates
The efficacy of traditional treatment of cancer, including nonspecific chemotherapy and molecular targeted therapy, has been unsatisfactory. Chemotherapy is highly toxic, causing considerable harm to the body of the patient. On the other hand, molecular targeted therapy possesses very low cytotoxicity and a poor ability to target genes.
Antibody-drug conjugates are designed to deliver cytotoxic agents directly, accurately transporting the cytotoxins required for antitumor activity. By using this method, many traditional problems associated with cancer therapy can be circumvented, including low selectivity, the narrow therapeutic window, and the rapid plasma clearance of chemotherapy.
A promising future for cancer therapy
The implementation of antibody-drug conjugates is changing the treatment patterns of many patients. Research is continuously being performed to increase the effectiveness of ADC’s mechanisms of drug resistance, manufacturing techniques, proper patient selection, and other factors. Further exploration of the treatment method could expand to focus on early-stage cancer patients and the treatment of other conditions.
How is an antibody-drug conjugate created?
ADCs are conjugates composed of three main elements: monoclonal antibodies, a cytotoxic agent, and an ADC antibody linker. A variety of methods for the generation of antibody-drug conjugates have been created in recent years, using various functional groups such as thiols, amines, alcohols, aldehydes, and azides.
Heterogeneous ADCs are typically synthesized by using thiols of cysteine residues and amines of lysines but are prone to losing the heterogeneity, potentially increasing the toxicity in circulation. In turn, homogeneous ADCs made through the catalysis of certain conjugation enzymes like AGT, BTG, aaRS, and Sial T show better stability. As more clinical experience on ADCs is attained, more efficient and specific ADC methods will be devised.
What are different antibody-drug conjugates?
Twelve different types of antibody-drug conjugates have been approved by the FDA as of April 2022. All approved ADCs are used for cancer therapy.
- Maker: Pfizer/Wyeth
- Brand name: Mylotarg
Mylotarg was originally given accelerated approval by the FDA in May 2000 to treat patients with CD33-positive adult acute myeloid leukemia (AML). This makes it the first antibody-drug conjugate to undergo clinical development.
Mylotarg was removed from the US market in 2010 by request of the FDA, but it remained available in Japan and other territories. The drug was re-approved for its use in the US and the EU in 2017 after further clinical trials were conducted. Mylotarg was approved to treat the newly diagnosed R7R CD33-positive AML.
- Maker: Seattle Genetics, Millenium/Takeda
- Brand name: Adcetris
Adcetris is an ADC that targets tumor cells expressing the CD30 antigen. This ADC is used in the treatment of relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL).
Initial clinical trials of Adcetris showed positive results, with 34% of patients achieving complete remission and tumor reductions being observed in the vast majority of patients (source). Adcetris is currently being researched as a substitute for the chemotherapy drug Oncovin.
- Maker: Genentech, Roche
- Brand name: Kadycla
Kadycla is based on the monoclonal antibody trastuzumab, commonly used to treat breast and stomach cancer. While trastuzumab can stop the growth of cancer cells on its own by binding to a HER2 receptor, Kadycla undergoes receptor-mediated internalization into cancerous cells, causing mitotic arrest and their death.
Kadycla was approved in the United States in 2013 for the treatment of adults with HER2-positive, metastatic breast cancer who have previously received other trastuzumab treatments (source). Patients in initial clinical trials experienced an improved median overall survival when compared to patients who received an alternate treatment method.
- Maker: Pfizer/Wyeth
- Brand name: Besponsa
Besponsa consists of monoclonal antibodies that target CD22 and it is used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). This ADC was approved for use in the US and EU in 2017.
Studies of the ADC performed in animals showed that the solution can cause serious harm to fetuses, even in doses lower than those common in a clinical setting. For this reason, pregnant women should not take the drug. Likewise, women undergoing treatment with Besponsa must avoid becoming pregnant while using it. It is advised that a woman taking Besponsa does not breastfeed for at least two months after her last dose of the medication.
- Maker: Genentech, Roche
- Brand name: Polivy
Polivy was first approved by the FDA in June 2019 to treat diffuse large B-cell lymphoma (DLBCL). It is meant to be used alongside a combination of bendamustine and rituximab. The drug was approved for medical use in the EU in January 2020.
The FDA’s approval of Polivy was based on the clinical trial NCT02257567 (source), which was conducted in the US, Canada, Europe, and Asia. Patients who participated in the clinical trials had previously experienced a relapse or had already been subjected to other treatments unsuccessfully.
- Maker: Astellas/Seattle Genetics
- Brand name: Padcev
Padcev is used in the treatment of transitional cell carcinoma, also known as urothelial cancer. The antibody used to manufacture Padcev is fully humanized and was created with the use of XenoMouse technology. Seattle Genetics provided and licensed the linker chemistry binding the antibody and the cytotoxic agent.
The FDA approved the use of Padcev in December 2019 and considers the drug to be a first-in-class medication. This means that a pharmaceutical product uses “new and unique mechanisms of action” to treat a particular condition. Furthermore, the application of Padcev has been granted accelerated approval, priority review designation, and breakthrough therapy designation (source).
- Maker: AstraZeneca/Daiichi Sankyo
- Brand name: Enhertu
Enhertu consists of the humanized monoclonal antibody trastuzumab and it has been licensed for the treatment of breast cancer, stomach cancer, and gastroesophageal adenocarcinoma. The drug was approved for its use in the US in December 2019, in Japan in March 2020, in the EU in January 2021, and in Australia in October 2021.
Unresectable or metastatic HER2-positive breast cancer patients who have received two or more anti-HER2 treatments are selectable for treatment with Enhertu. Likewise, gastric or gastroesophageal carcinoma patients who have previously received a trastuzumab treatment are eligible for Padcev treatment.
- Maker: Immunomedics
- Brand name: Trodelvy
Considered by US and EU authorities as a first-in-class medication, Trodelvy is used for the treatment of metastatic triple-negative breast cancer and metastatic urothelial cancer. Similar to the aforementioned antibody-drug conjugates, the use of Trodelvy is currently reserved for patients who have undergone other treatments unsuccessfully.
Trodelvy may cause harm to a developing fetus or a newborn baby. Women are advised to avoid breastfeeding while on Trodelvy for at least a month after they have received their last dose.
- Maker: GlaxoSmithKline
- Brand name: Blenrep
Blenrep is meant for the treatment of relapsed and refractory multiple myeloma (MM). This antibody-drug conjugate binds to B-cell maturation antigens (BCMAs) on myeloma cell surfaces, causing cell-cycle arrest and introducing a cytotoxic agent.
The drug was approved for medical use in the US and the EU in August 2020. Eligible patients must have first undergone four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
- Maker: AstraZeneca
- Brand name: Lumoxiti
Lumoxiti is an anti-CD22 immunotoxin used to treat adults with relapsed or refractory hairy cell leukemia (HCL). To be eligible for Lumoxiti treatment, patients must have previously received two systemic therapies, including a purine nucleoside analog treatment. The FDA approved Lumoxiti in September 2018.
- Maker: ADC Therapeutics
- Brand name: Zynlonta
This monoclonal antibody conjugate medication is used in the treatment of relapsed or refractory large B-cell lymphoma. Zynlonta is composed of a humanized antibody that targets the protein CD19. It was first approved for medical use in the US in April 2021. Because of the way the drug is implemented, it may be a suitable treatment for patients unable to undergo CAR-T cell therapy (source).
- Maker: Seagen Inc.
- Brand name: Tivdak
Tivdak is meant for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Its administration method consists of an IV infusion every 3 weeks. The drug was approved for medical use in the US in September 2021.
Patients treated using Tivdak may be at risk of developing an ocular toxicity-related condition. In clinical trials, forms of ocular toxicity such as dry eyes, conjunctivitis, corneal damage, and blepharitis were observed (source).