Antibody-drug conjugates (ADCs) are a novel class of targeted cancer therapeutics. They allow for targeted delivery of toxic payloads to cancer cells while sparing normal tissues. Therefore, ADCs can be used to treat various cancer types with improved efficacy and reduced side effects.
In this blog, we’ll look at what antibody-drug conjugates are, how they’re made, and recent advances in the field.
What is an Antibody-Drug Conjugate?
ADCs are a type of targeted cancer therapy composed of three parts: a monoclonal antibody, a payload, and a linker.
Monoclonal Antibody
Antibodies are Y-shaped molecules produced naturally by the body’s immune system. They identify, bind to, and neutralize specific viruses and bacteria. Monoclonal antibodies created in the lab have the same effect. Each one is designed to recognize and bind to a specific target, such as antigens on the surface of cancer cells. In an ADC, the monoclonal antibody is the component responsible for the specificity of the treatment.
Ideally, the monoclonal antibody in an ADC would detect a protein only present on cancer cells and nowhere else. Practically, other non-cancer cell types will also express the protein. For example, the ADC gemtuzumab ozogamicin uses a monoclonal antibody that recognizes a protein called CD33 expressed in cells of patients with acute myeloid leukemia. However, CD33 is also normally expressed in bone marrow cells that make blood cells. Consequently, patients taking this ADC may experience symptoms related to producing fewer blood cells.
Payload
The payload of an ADC is a cytotoxic drug that can kill cells by interfering with their DNA, metabolism, or other functions. Relying on the monoclonal antibody for selectivity, the payload of an ADC can be a nonspecific cell killer. For example, there are two approved ADCs (gemtuzumab ozogamicin and inotuzumab ozogamicin) whose payload is a protein of the calicheamicin class (originally isolated from bacteria in a rock sample from Texas). Calicheamicins act by chopping DNA and have been shown to effectively kill cells of any type. The use of calicheamicins, and other potent drugs, are only possible due to the specificity afforded by the attached monoclonal antibody.
Linker
The linker is a chemical structure that links the payload to the antibody while maintaining the stability of both components. It is designed to release the drug molecule selectively and efficiently only in the target tissue or cell, thereby minimizing systemic toxicity. Depending on the specific linker used, the linker can be cleaved by chemical hydrolysis, enzymatic cleavage, or redox reactions. The linker is a critical factor in determining the pharmacokinetics, biodistribution, and therapeutic efficacy of an ADC. Therefore, selecting an appropriate linker is crucial for successfully developing an ADC.
How Do Antibody-Drug Conjugates Work?
ADCs work by exploiting antibodies to selectively deliver drugs to cancer cells while sparing healthy cells. The monoclonal antibody recognizes and binds to a specific antigen on the cell surface. To increase the chance that a monoclonal antibody will bind to cancer cells, researchers select the specific monoclonal antibody by considering the type of cancer being targeted. After the monoclonal antibody binds to a cell, it triggers a process called internalization in which the cell engulfs the ADC. The linker is cleaved or degraded inside the cell, releasing the payload. The cytotoxic drug payload can then exert its effect on the cell to kill it. This mechanism allows ADCs to achieve higher efficacy and lower toxicity than conventional chemotherapy, which affects both normal and cancer cells.
What Are the Challenges in Manufacturing Antibody-Drug Conjugates?
ADCs function by combining the specificity of an antibody with small molecule drugs that are toxic to cells. Because of the potency of the small molecules being used as a payload, the stability of the linker is critical. The FDA has issued guidance for biopharma to ensure that safety is prioritized early in development.
One of the major challenges in making ADCs is selecting the appropriate monoclonal antibody, linker, and payload. The antibody must recognize a cancer-specific antigen and exhibit rapid internalization. Additionally, the antibody should not elicit an immune response or exhibit non-specific binding to other cells or tissues. Developing an effective antibody can be time-consuming and expensive, and failure to select a suitable antibody can lead to poor therapeutic efficacy or toxicity. The linker must be stable in circulation but release the drug efficiently and selectively in the cancer cell. The payload must have high potency and a mechanism of action independent of the cancer cell’s intrinsic resistance mechanisms. Choosing the right combination of these three components for a cancer type can involve systematic trials of multiple combinations. In addition, different cancers may require different combinations of monoclonal antibodies, payloads, and linkers to produce an effective treatment.
Controlled Production
Another challenge in making ADCs is achieving the optimal ratio of drug to antibody, also known as the drug-to-antibody ratio (DAR). The DAR affects the pharmacokinetics, efficacy, and toxicity of the ADC. It must be carefully controlled during the conjugation process. A low DAR may result in low or insufficient potency, while a high DAR may cause aggregation, immunogenicity, or off-target effects.
Like other pharmaceutical and biopharmaceutical manufacturing, the production process must ensure that the final product is homogeneous, reproducible, and stable. The specifics of ADC manufacturing pose additional challenges. For example, each ADC molecule must have the same number and location of drug molecules attached to the antibody. This can be achieved by using site-specific conjugation methods, which target specific amino acids or engineered motifs on the antibody. The ADC must also remain stable during manufacturing, storage, and administration. ADCs have additional considerations for stability, including a tendency for the molecules to aggregate. Biopharmaceutical companies must carefully evaluate the stability of the ADC under different conditions and optimize the formulation to ensure maximum stability and efficacy.
How Many Antibody-Drug Conjugates Are on the Market?
As of March 2023, the FDA has approved 12 ADCs for the treatment of cancer. Two of the 12 ADCs (trastuzumab emtansine and trastuzumab deruxtecan) use the trastuzumab monoclonal antibody, which binds to HER2, to target HER2-positive breast cancer cells. The other 10 ADCs use monoclonal antibodies that recognize different target proteins that are overexpressed in various cancer types, including targeting CD19 for B-cell lymphoma (loncastuximab tesirine) and nectin-4 for urothelial cancer (enfortumab vedotin).
In addition to the 12 approved ADCs, over 240 active clinical trials are testing new ADCs and existing ADCs for different cancer types. Given the size of this pipeline and the specificity and efficacy of ADCs, new ADCs and label expansions for approved ADCs are likely forthcoming.
What’s Next for Antibody-Drug Conjugates?
ADCs face multiple unique challenges, including drug resistance, toxicity, heterogeneity, and immunogenicity. Researchers are exploring novel strategies to counter these challenges, such as combination therapy, multispecific antibodies, and alternative payloads.
Combination therapy pairs ADCs with other anticancer agents, such as chemotherapy, immunotherapy, or targeted therapy, to enhance the efficacy and overcome the resistance of ADCs. For example, a phase I trial showed that the combination of T-DM1 (an ADC targeting HER2) and pertuzumab (a HER2-targeted antibody) improved the survival of patients with HER2-positive breast cancer compared to T-DM1 alone.
Multispecific antibodies can bind to two or more antigens simultaneously. This further increases the specificity and potency of ADCs. For example, using a bispecific antibody that targets both HER2 and the prolactin receptor PRLR increased the efficiency of cancer cell death compared to a HER2-specific ADC.
Researchers are also exploring the use of alternative payloads. In addition to drugs with different mechanisms of action or chemical properties than the conventional cytotoxic drugs used in ADCs, research is investigating more exotic payloads. These include options like using a payload of a carbon nanotube filled with radioactive metals or nanocarriers that can deliver a cocktail of different cytotoxic drugs.
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That’s a Wrap
In summary, ADCs are targeted cancer therapeutics that offer a promising strategy for treating various types of cancers with improved efficacy and reduced side effects. They consist of three components: a monoclonal antibody, a payload, and a linker. The monoclonal antibody selectively recognizes and binds to a specific antigen present on the surface of cancer cells. This triggers internalization, followed by the cleavage of the linker and the release of the payload to exert its effect on the cell. One of the major challenges in making ADCs is selecting the appropriate monoclonal antibody, linker, and payload. Another challenge is achieving the optimal ratio of drug to antibody. Continued research and clinical developments are further enhancing the potential of ADCs for cancer treatment.
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