ADC: All you need to know about antibody-drug conjugates

Antibody-drug conjugates (ADCs) are among the most promising modalities in modern biopharmaceutical development. Compared to conventional chemotherapy, ADCs enable a highly targeted approach, destroying cancer cells while largely sparing healthy tissue.
By linking a monoclonal antibody to a potent cytotoxic payload, an antibody-drug conjugate functions as a precision delivery system, transporting the drug directly to the target cell for lysosomal degradation. This selective mechanism has earned ADCs the nickname “biologic missiles”. Several ADCs are already established in the treatment of myeloid leukemia and refractory metastatic breast cancer, with many more advancing through clinical trials. As ADC design continues to improve in terms of stability and efficacy, their role in oncology pipelines is rapidly expanding.[[1]] [[2]] 

In this article, we cover the ABC of ADCs: from key components and mode of action to facts you probably did not know about antibody-drug conjugates. At the same time, critical manufacturing questions emerge: How can an antibody-drug conjugate be filled, frozen and protected throughout processing whilst maintaining its product integrity?

Antibody Drug Conjugate Definition

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. This innovative approach in drug development targets cancer cells with high precision.

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: 
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.

What makes up an antibody-drug conjugate?

There are three main components of antibody drug conjugates: There is the antibody, the drug or payload and the linker. This is how they work:

The antibody

Antibodies have the ability to target potential threats through high binding specificity to an antigen. Monoclonal or bispecific antibodies are able to bind to proteins and receptors on the cell surface of cancer cells.

Payload

The drug which is used to initiate the desired response and fight the cancerous cells is also referred to as cytotoxic payload, like calicheamicin or maytansinoids for example. It is released once the antibody has docked onto the tumor cell.

Linker

The non-cleavable linker is the binding agent between payload and antibody. Its stability is an important factor in the ADCs efficacy and has to be able to be maintained even in precarious conditions to make sure the cytotoxic agent can be delivered to the cancerous cells. At the same time it has to be able to release the payload once the antibody has bound to the cancer cell by disulfide reaction. The linker also needs to be able to release the payload once the antibody has bound to the cancer cell. This process often involves enzymatic activity, as certain linkers are designed to be cleaved by specific enzymes present within the cancer cells.

Mechanism of action: How does an ADC work?

Antibody-drug conjugates selectively kill cells. An ADC 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 targeting 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. [[5]] [[6]]

Examples of Antibody-drug conjugates – read more

FDA approved antibody-drug conjugates

There are currently 14 ADC products for cancer treatments that have gained the FDA certificate. 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 (food and drug administration) approval. ADCs offer promising treatments for various types of cancer, including lung cancer, gastric cancer and breast cancer, by targeting tumor cells while minimizing damage to healthy cells.

These novel therapies carry certain risks, such as potential side effects, including thrombocytopenia (low platelet count), which can impact blood clotting and overall patient safety. Nevertheless, ADCs represent a significant advancement in targeted cancer therapy, providing new avenues for more effective and safer treatment options.

As ADCs are a relatively new class of drug, more approvals are expected in the near future. Below, you can find the names and producers of approved ADCs:

1. Gemtuzumab ozogamicin (Pfizer/Wyeth)
2. Brentuximab vedotin (Adcetris®, Seattle Genetics, Millenium/Takeda)
3. Trastuzumab emtansine (KADCYLA®, Genentech, Roche)
4. Inotuzumab ozogamicin (Pfizer/Wyeth)
5. Polatuzumab vedotin (Genentech, Roche)
6. Enfortumab vedotin (Astellas/Seagen)
7. Trastuzumab deruxtecan (Enhertu®, AstraZeneca/Daiichi Sankyo)
8. Sacituzumab govitecan (Trodelvy®, Gilead Sciences)
9. Belantamab mafodotin (Blenrep®, GlaxoSmithKline)
10. Moxetumomab pasudotox (Lumoxiti®, AstraZeneca)
11. Loncastuximab tesirine (Zynlonta®, ADC Therapeutics)
12. Tisotumab vedotin-tftv (Tivdak®, Seagen Inc. and Genmab)
13. Mirvetuximab soravtansine (Elahere™, ImmunoGen Inc.)
14. Datopotamab deruxtecan (Datroway™, AstraZeneca / Daiichi Sankyo)
15. Telisotuzumab vedotin (Emrelis™, AbbVie)

Sources: [[7]] [[8]] [[9]]

FDA approved ADCs

Manufacturing of ADCs explained

Antibody drug conjugates are not so easy to make. 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 site-specific 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. In vitro testing plays a crucial role in evaluating the ADC’s effectiveness, stability, and potential side effects, allowing for the optimization of the manufacturing process. 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.

ADC manufacturing & the challenges to overcome

Companies in ADC manufacturing

Pfizer, AstraZeneca, Gilead Sciences & Seagan and many more are big pharma manufacturers for antibody drug conjugates. 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.

Antibody-Drug Conjugate Companies

ADCs cytotoxicity as a challenge

Operator safety due to ADCs cytotoxicity is a big challenge in manufacturing. 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 personnel involved in the process, ADCs must be handled in securely closed systems at all times. ADC production has to follow strict GMP standards to guarantee safe manufacturing practices for personnel and product use for cancer patients.

Aseptic processing and filling techniques must fulfill requirements to grant GMP-readiness and operator safety. To take the strain off staff and supply chains, single-use technologies are used by many of the key CDMOs or CMOs.

How to provide operator safety

Safe handling of Antibody Drug Conjugates

Single-use technologies offering closed fluid transfer systems improve antibody-drug conjugate manufacturing. To make sure the drug substance 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 for fluid management and controlled freezing and cold chain of ADCs 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.

Safe ADC fluid management

Trends & outlook for antibody-drug conjugates

The advantages antibody‑drug conjugates offer in the treatment of solid tumors continue to drive strong industry investment. Research increasingly focuses on new payloads and antibodies with higher specificity, enabling more effective and differentiated therapies.

For indications such as B‑cell lymphomas, highly selective antitumor activity is essential to achieve efficacy while minimizing systemic toxicity. In parallel, CMOs are advancing production technologies for cytotoxic agents and improving control over critical quality attributes, including the drug‑to‑antibody ratio and ADC homogeneity.

Despite growing demand, only a limited number of CMOs can currently manufacture ADCs efficiently. The cytotoxic nature of the payload and complex conjugation steps have accelerated the adoption of single‑use technologies among leading players.
As manufacturing is often distributed across specialized partners, supply‑chain complexity remains a challenge. However, increasing capacity and specialization are expected to reduce bottlenecks as the market matures.

At the same time, the value of modern ADCs continues to rise on a per‑milliliter basis. Higher drug‑to‑antibody ratios, more potent payloads and advanced linker technologies are steadily increasing both complexity and risk. Looking ahead, the shift toward next‑generation bioconjugates will further raise the bar for robust and scalable manufacturing strategies.

Solutions for safe ADC processing

Key takeaways

• Antibody‑drug conjugates (ADCs) combine biologics with highly potent cytotoxic payloads, enabling targeted cancer therapy but increasing complexity across development and manufacturing.
• ADC handling leaves little room for error: High potency, small batch sizes, and extreme product value demand precise, closed, and well‑controlled fluid handling and containment.
• Cold chain integrity is critical for ADC quality: Temperature control and adsorption‑safe materials are essential throughout freezing, storage and transport.
• Modern ADC manufacturing relies on robust, GMP‑ready single‑use systems
  to minimize contamination risk, protect operators, and safeguard high‑value drug substances.

References

1. Antibody–Drug Conjugate (ADC) Clinical Pipeline: A Review, http://dx.doi.org/10.1007/978-1-62703-541-5_1, Published 2013-08-01
2. Antibody-drug conjugates as novel anti-cancer chemotherapeutics, https://pubmed.ncbi.nlm.nih.gov/26182432/, Published 12.06.2015
3. Unlocking the potential of antibody–drug conjugates for cancer therapy, http://dx.doi.org/10.1038/s41571-021-00470-8, Published 2021-02-09
4. Drug-Linkers in Antibody–Drug Conjugates: Perspective on Current Industry Practices (Zhang), https://colab.ws/articles/10.1021/acs.oprd.3c00136, Published 29.06.2023
5. Antibody drug conjugate: the “biological missile” for targeted cancer therapy, http://dx.doi.org/10.1038/s41392-022-00947-7, Published 2022-03-22
6. Antibody‐drug therapeutic conjugates: Potential of antibody‐siRNAs in cancer therapy, http://dx.doi.org/10.1002/jcp.28490, Published 2019-03-25
7. Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index, http://dx.doi.org/10.1158/1078-0432.CCR-19-0272, Published 2019-04-12
8. Antibody-Drug Conjugates in Cancer Therapy, http://dx.doi.org/10.1146/annurev-med-050311-201823, Published 2012-10-09
9. Biopharma PEG, https://www.biochempeg.com/article/74.html, Published 07.05.2024

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