April 24, 2023
Antibody drug conjugates (ADCs) are a rapidly growing field of interest in biopharmaceutics. In comparison to conventional chemotherapy treatments, ADCs have the potential to destroy cancerous cells without damaging healthy cells in the process.
Through a monoclonal antibody that is linked to the cytotoxic drug, it becomes possible to target cells more efficiently and deliver the cytotoxic drug where it is needed for lysosomal degradation and kill cancer cells. Because of this mechanism, ADCs are also referred to as “biologic missiles”. Several ADCs are already successfully used in the treatment of myeloid leukemia or refractory metastatic breast cancer. Many others are in clinical trials and waiting for their FDA approval.
In this article we will give you an introduction to this important and rapidly growing field. We will inform you about the different components and functions of ADCs and provide you with seven facts you probably didn't know yet about antibody drug conjugates.1
Antibody drug conjugates are highly effective drug substances used in the treatment of various cancers. They consist of a combination of a monoclonal antibody (mAb) and a small molecule drug which have been connected through a chemical linker.
There are only a few known payloads that are stable and potent enough to be suitable for ADCs, yet. Often payloads are used that are too toxic to be used as a stand alone drug. One example is monomethyl auristatin A MMAE, which inhibits microtubule polymerization in the cancer cell’s cytoplasm. Further, there are cytotoxic drugs which involve amatoxins, anti tubulin (MMAF) and alkylating agents. It is important to regulate pharmacokinetics and selectivity to ensure a successful conjugate without unwanted “bystander killings” of healthy cells.
Read more:
What are antibody drug conjugates?
Bioconjugation simply explained
ADC technology simply explained
While the optimization of the antibody and drug conjugate facilitates to target cancer cells more efficiently without causing undesired side effects like damaging normal tissue, these are still common problems in conventional chemotherapy treatments. This is why ADCs have a promising future ahead. Many pharmaceutical companies therefore invest a lot of money and time in pushing progress in the research and clinical development of improved antibodies and efficient manufacturing techniques.2
There is the antibody, the drug or payload and the linker. This is how they work:
An antibody drug conjugate is the combination of mAbs’ highly specific targeting and cell killing abilities of cytotoxic agents in anticancer drugs. To fight cancer most efficiently without harming healthy cells in the process, an antibody is coupled with the drug through a chemical link. This causes higher malignancy selectivity while improving drug tolerability.
As soon as the mAb recognizes the potential threat, it targets the cancerous cell. For circulating ADCs to recognize it, the antigen should ideally be a surface or extracellular antigen, rather than an intracellular one. Then the peptide binds to the specific target antigen on the surface. Through this mechanism of action a reaction is triggered. The cancer cell receives the peptide signal and absorbs the antibody linked to the cytotoxic agent. After the internalization of the ADC, the cytotoxic agent initiates cell death.3 4
Due to new possibilities through technological advancements, a rapidly growing number of ADCs is currently in preclinical development or in clinical trials and pharmacologic evaluations, waiting for their FDA approval.
ADCs are a relatively new class of drug. So more approvals are to be expected. Find its names and producers of approved ADCs below:
1. Gemtuzumab ozogamicin (Pfizer/Wyeth)
2. Brentuximab vedotin (Seattle Genetics, Millenium/Takeda)
3. Trastuzumab emtansine, KADCYLA® (Genentech, Roche)
4. Inotuzumab ozogamicin (Pfizer/Wyeth)
5. Polatuzumab vedotin (Genentech, Roche)
6. Enfortumab vedotin (Astellas/Seagan)
7. Trastuzumab deruxtecan (AstraZeneca/Daiichi Sankyo)
8. Sacituzumab govitecan (Immunomedics)
9. Belantamab mafodotin (GlaxoSmithKline)
10. Moxetumomab pasudotox (AstraZeneca)
11. Loncastuximab tesirine (ADC Therapeutics)
12. Tisotumab vedotin-tftv (Seagen Inc.)5
Antibody drug conjugate manufacturing is a highly complex and laborious process which includes not only antibody production, but also chemical synthesis and ADC conjugation. To explain the overall concept in a simplified manner, the complicated trial can be broken down to these steps:
1. Antibody production: The antibody with the desired qualities is manufactured and expressed in a host cell line (i.e. hybridoma cells, mammalian cells or microbial cell lines).
2. Chemical synthesis: Linker molecules are developed and modified to achieve a high level of stability which is needed in critical pH conditions and different serum protease inhibitors.
3. ADC conjugation: The conjugation of the drug and antibody is achieved in a reactor. The ADC is then filtered and purified through chromatography systems to get rid of any impurifications that could change the efficacy of the finished product. In the finishing step the ADC is filled into aseptic bioprocess containers.
The drug to antibody ratio (DAR) is an important point to consider in the manufacturing of ADCs to guarantee their efficacy. During the whole process current good manufacturing practices (cGMP) have to be operated at all times to guarantee a safe and effective product. If any impurities remain or a part of the ADC is contaminated during the process, the safety of the drug for the patient can no longer be guaranteed.
The production and research on ADCs have quickly become a rapidly growing field of interest. Targeted oncology therapeutics have become one of the most promising sectors in the biopharmaceutical industry due to their advantages over common chemotherapeutic treatments.
There are several companies which play a key role in the research, development and production of ADCs. To name just a few of the most influential companies in ADC production, Pfizer, AstraZeneca, Gilead Sciences and Seagan are among the names that have to be mentioned.
Pfizer Inc. was one of the first providers of ADCs and continues its ambitious development of antibodies for this purpose. Just as AstraZeneca, their main focus remains on oncological drugs. As the second leading patent filer for ADCs on the market, Gilead Sciences continues as one of the most influential companies in ADC development. Further, big advances on the treatment of metastatic urothelial cancers have been made through a collaboration by Seagan and Astella Pharma.
The many benefits of ADCs are however associated with a big risk due to the extreme toxicity. ADCs are categorized as highly hazardous pharmaceutical products due to cytotoxicity of their payloads.
As this poses a major health threat on the staff involved in the process, ADCs have to be operated in securely closed systems at all times. ADC production has to follow strict cGMP standards to guarantee safe manufacturing practices for staff and product use for cancer patients.
Further, it relies on aseptic processing and filling techniques. To fulfill all of these requirements, a lot of time and money has to be invested. To take the strain off staff and supply chains, single-use technologies are used by many of the key CDMOs or CMOs.
To make sure drug efficacy is fully functional and the chemotherapeutic drug is free of any impurities, aseptic production has to be a given in the manufacturing of ADCs. This includes aseptic production tools and filling devices and an aseptic environment (clean room). These standards make the manufacturing of ADCs a cost intensive and laborious process. As the process is prone to human errors, the risk of product loss increases the pressure on manufacturers.
Single-use technologies help to improve safety conditions for staff and streamline the process in order to prevent possible bottlenecks. Through fully automated solutions and fluid management with single-use equipment it becomes possible to manufacture and finish products without exposure to the environment. The risk of human error and accidental contact with hazardous substances is reduced to a minimum.
More readings about safe processing in ADC manufacturing:
Safe filling and aliquoting of ADCs
Controlled freezing of ADCs
Process Safety in fluid management of ADCs
With the many advantages ADCs bring to the table in the treatment of solid tumors it does not surprise that progress in the research for new molecules as well as antibodies with higher specificity lies in the interest of many pharma companies.
Especially for diseases like B-cell lymphomas, a high specificity in antitumor activity is extremely important to combat the disease efficiently. Further, CMOs are always on the lookout for new and improved production techniques for cytotoxic agents. As the efficacy of ADCs also relies on the drug to antibody ratio, controlling the homogeneity of ADCs is another focus for many CMOs.
However, there are only a few CMOs who are able to produce ADCs efficiently. To overcome challenges in manufacturing due to the cytotoxicity of the drug and the potentially slow rate of antibody production, leading key players in this field rely on single-use technology.
As most CMOs have specified in one aspect of ADC manufacturing, often many partners are needed in the production. This can lead to bottlenecks in the supply chain and - in consequence - to production loss because time plays an important role in the half life of antibodies. However, as the sector keeps on growing and new companies are entering the market, this problem will be overcome.
In antibody-drug conjugates the therapeutic index refers to the ratio between the maximum tolerated dose of the cytotoxic payload derivative and the minimum effective dose required for the desired therapeutic effect. ADCs have a narrow therapeutic index due to the potent nature of the payload, and therefore require careful dosing and monitoring to ensure safety and efficacy.
ADCs are used as anti-HER2 therapies. ADCs can target the HER2 protein on cancer cells and deliver a cytotoxic drug to kill them. There are currently several anti-HER2 ADCs approved for the treatment of HER2-positive breast cancer, including T-DM1 and trastuzumab deruxtecan.
ADCs are not considered traditional immunotherapy, as they do not directly stimulate the immune system. However, they are a type of targeted therapy that can be used in conjunction with immunotherapy to enhance treatment efficacy.
The first FDA-approved ADC was gemtuzumab ozogamicin, which was approved in 2000 for the treatment of acute myeloid leukemia. However, it was later withdrawn from the market and then reintroduced in 2017 with new dosing recommendations.
Director New Products, Innovation & Product Line Management
