The concept of ADC (Antibody-Drug Conjugates) has been around for a long time, but the ADC industry has struggled in the past due to the high technical threshold required for their synthesis, the long-term off-target, the discovery of specific antigens and other technical problems. It was not until recent years that the rapid development of ADC drugs began, after many years of experiments and iterations by scientists on how to synthesize ADC drugs, improve safety, and reduce off-target and toxic side effects.
ADC drugs have both the tumor targeting of antibody drugs and the powerful killing effect of small molecule drugs, showing excellent clinical efficacy in breast cancer, urothelial carcinoma, gastric cancer, hemoma and other fields, bringing more treatment options for tumor patients who have failed multi-line treatment. With the intensive marketing of various ADC drugs in recent years, especially the approval of the third-generation ADC drugs represented by Enhertu and Trodelvy, more and more innovative pharmaceutical companies have increased their layout in this field. ADC therapies have become one of the hot research directions in the field of tumor therapy today. Here we will introduce the current development and future prospects of ADC therapies.
The Concept of ADC Drugs
ADC drugs are called "biological missiles", which consist of three parts: antibodies, payloads, and linkers. Among them, the antibody acts as a "guidance system" and is responsible for selectively recognizing antigens on the surface of cancer cells. The payload (that is, small molecule cytotoxic drugs) acts as a "warhead" and is responsible for killing cancer cells. The linker is responsible for connecting the antibody and the payload.
Timeline of important events for ADC drugs
(Source: Antibody drug conjugate: the “biological missile” for targeted cancer therapy)
Five Elements of ADC Drug Design
ADC is a complex structure composed of three parts: antibody, linker and payload, which determines that its preparation process will be more complicated. During the preparation and production process, small molecular toxins need to undergo multiple synthetic steps, dissolve in a variety of solvents, and maintain their chemical structure and properties during these processes. In order to enable ADC drugs to function effectively and achieve the expected efficacy and safety, the target, antibody, linker, payload, conjugation methods and reasonable combination among them should be focused on in the design and development of ADC. The success of ADC drugs often depends on the design of these five elements.
Target selection is a key part of ADC drug design and the primary consideration in ADC development. An ideal target should have the following characteristics: The first is tissue specificity, the target antigen should be expressed at a high level in tumor cells, and not or lowly expressed in normal tissues. Then second is the stability. That is, the target antigen is not easy to fall off from the target tissue, so as to prevent the combination of antigens with ADC drugs in the internal circulation system, thereby reducing the amount of aggregation to the target site, affecting the efficacy and safety of the drug. The third is efficient induction of internalization. After the antibody binds to the surface antigen of tumor cells, the ADC-antigen complex must be able to effectively induce the internalization process and enter the tumor cells to achieve rapid release of the payload.
In theory, ADC drugs can release toxins outside tumor cells, killing tumor cells through the "bystander effect" without internalizing the cells. In fact, most of the effectiveness of ADC drugs is based on internalized drug release. Therefore, after the antibody in an ADC drug binds to the surface antigen of a tumor cell, the ADc-antigen complex must be able to effectively induce the internalization process, enter the tumor cell, and achieve the effective release of small molecule drugs through appropriate intracellular transport and degradation processes.
HER2 has become a hot target for research and development worldwide. Among the 15 drugs on the market, the drug targets for solid tumors include HER2, trop2, nectin4, EGFR, and the targets for hematoma include CD19, CD22, CD33, CD30, etc. Among them, there are 3 drugs targeting HER2, followed by CD22, a total of 2 drugs. As of December 2022, there are more than 60 ADC drugs targeting HER2 in the world, accounting for nearly 40%.
ADC antibodies can specifically bind to the target antigen on the surface of tumor cells and be highly internalized into cells, which requires the following characteristics: The first is target specificity and high endocytosis. Antibodies should have high antigen specificity and affinity, and achieve effective internalization to release the payload in cells. The second is low immunogenicity, which needs to achieve the minimum immunogenicity through the selection of humanized or whole human antibodies. The third is long circulation half-life, ADC drugs in the blood should have a long circulation time to smoothly enter the tumor cells.
IgG1 is currently the most mainstream ADC antibody. The antibodies of ADC drugs are mainly immunoglobulin G (IgG) antibodies, including four subtypes of IgG1, IgG2, IgG3 and IgG4. After binding to target cells, IgG1 can induce various immune responses such as ADCC and CDC. It has excellent characteristics such as strong stability and long half-life, and has become the mainstream choice of ADC drugs. Of the 15 drugs already on the market, 13 use IgG1 as the antibody, and the remaining two use IgG4 (both from Pfizer).
The emergence of antibody-based drugs has enabled substantial progress in the treatment of a variety of diseases, including cancer, autoimmune diseases, cardiovascular diseases, benign blood diseases and bone diseases. Antibody fragments and bispecific antibodies offer promising therapeutic prospects for innovative therapies. Antibodies need to meet high specificity, strong target binding ability, low immunogenicity, and low cross-reactivity to achieve more efficient uptake of ADC drugs by tumor cells and longer half-life of ADC drugs in serum.
The linker is used to connect the monoclonal antibody and the payload, and its chemical properties and conjugation sites are crucial to the stability of the ADC drug and the release of the payload. The linker needs to have the following three characteristics: (1) The linker has stability in the blood; (2) The linker can accurately release the warhead at the target location; (3) The linker should have certain hydrophilicity.
ADC has undergone three generations of upgrades. According to the release mechanism of the load, the linkers gradually differentiates into cleavable linkers and non-cleavable linkers. Cleavable linkers have become the mainstream trend. Cleavable linkers can be divided into two categories: enzyme-dependent and chemical-dependent. They have a bystander effect and can kill cells with low antigen expression in heterogeneous tumors. They are the mainstream direction of current drug development. Twelve of the 15 marketed drugs use degradable linkers. Among them, drugs such as Enhertu and Aidixi are cleavable linkers, and their catabolites can pass through the cell membrane to exert a bystander effect.
Payload is one of the most critical components of ADC drugs, and it is the decisive factor for ADC drugs to play the role of target cell killing. The payload should have the following characteristics: first, it is highly cytotoxic. The amount of toxin ingested at the tumor site is very low. Toxin molecules should play the highest cytotoxic effect at a low concentration and kill tumor cells efficiently. The second is modifiability, the structure of the drug can be modified to ensure that it can be coupled with a linker. The third is high stability, the target of the toxin molecule is mainly located in the cell, and the toxin cannot be degraded and inactivated in the biochemical environment after being released into the cell. Fourth, hydrophobic and membrane-permeable, toxins with these characteristics can penetrate the cell membrane to play a bystander effect and kill cells with low expression of surrounding antigen after being released in the cell.
5. Conjugation Methods
Conjugation technology connects antibodies and small molecule toxins through linkers, involving chemical reactions, antibody modification and transformation and other related technologies. The conjugation technology adopted by ADC drugs is closely related to its final drug-to-antibody ratio (DAR), and the value and distribution of DAR will significantly affect the properties of ADC drugs. Too large a DAR may lead to the accumulation of ADC drugs and then be cleared in the circulatory system. Too small a DAR may cause ADC drugs to fail to achieve the best therapeutic effect. DAR between 2 and 4 is the best choice for ADC drugs.
Popular Targets For ADC Drugs
15 marketed ADC drugs correspond to 11 targets, which are CD33, CD30, HER2, CD22, CD79b, Nectin-4, BCMA, EGFR, CD19, Tissue Factor and FRα.
ADC targets approved by FDA
In terms of current target trends, the most popular target in the ADC field is HER2, followed by the popular Trop-2. At the same time, Claudin 18.2, a popular target in the field of gastric cancer, is also another popular target in current research and development. In the competition for the development of Claudin 18.2 target, in addition to ADC, many new attempts have also emerged, such as CAR-T. However, under the current situation that there is no obvious advantage in the development of efficacy, it is speculated that the market will be more inclined to cheaper ADC drugs, and it may be more difficult to commercialize CAR-T for the treatment of solid tumors.
HER2, short for human epidermal growth factor receptor-2, is a receptor tyrosine kinase on the surface of cell membranes that can regulate cell proliferation and differentiation. At present, abnormal expression of HER2 has been found in breast cancer, ovarian cancer, gastrointestinal cancer, lung cancer and non-small cell cancer. Tumors with high expression of HER2 show strong ability to metastasize and infiltrate, are less sensitive to chemotherapy, and are prone to relapse.
There are several HER2 AdCs on the market, including Kadcyla, Enhertu and disitamab vedotin. Kadcyla is the first HER2 ADC drug, which can significantly reduce the risk of recurrence by 50% after breast cancer surgery. It has a significant effect in the treatment of breast cancer, but it is not effective in the treatment of gastric cancer. Enhertu is currently the most effective HER2 ADC drug, and its clinical trials for breast cancer and gastric cancer have all been successful. In particular, Enhertu beat Kadcyla in the Phase III head-to-head clinical trial (DESTINY-Breast03) for the treatment of breast cancer. Disitamab vedotin has been approved for marketing, and its efficacy data is comparable to that of Kadcyla.
TROP-2, short for trophoblast cell surface antigen 2, promotes the growth, proliferation and metastasis of tumor cells mainly by regulating calcium ion signaling pathway, the expression of cyclin and reducing fibrin adhesion. TROP-2 is highly expressed in a variety of tumors, such as pancreatic cancer, breast cancer, colon cancer, bladder cancer, oral squamous cell carcinoma and ovarian cancer, and its high expression is closely associated with shortened survival and poor prognosis of tumor patients. Trodelvy, a marketed TROP-2 ADC drug, reduced the risk of disease or death by 59% and extended overall survival to 10.9 months.
Claudin18.2 belongs to a family of Claudin integrin membrane proteins that exist in the tight junction between epithelial and endothelial. Claudin18.2 is usually buried in the gastric mucosa and cannot be contacted and bound by antibodies in normal tissues. However, the occurrence of malignant tumors will lead to the destruction of the tight junction. The Claudin18.2 epitope on the surface of tumor cells was exposed and became a specific target. Claudin18.2 is highly expressed in gastric cancer, as well as pancreatic, esophageal, and lung cancers. The current layout of Cladin18.2 ADC drugs, the fast progressing ones are CMG901 and SHR-A1904.
Marketed Drugs And Market Size For ADC Drugs
1. Marketing ADC Drugs
As of December 2022, 15 ADC drugs have been approved worldwide. The world's first ADC drug, Mylotarg, was approved in 2000, but it was withdrawn in 2010 due to fatal liver injury, and it was re-launched in 2017 after optimizing the drug regimen to improve efficacy and safety. From 2001 to 2010, no ADC drug was approved for marketing in the world, and the development of the industry entered a low period. With the continuous advancement of technology, the second-generation ADC drug represented by Adcetris was launched in 2011, and a total of 4 products were launched from 2011 to 2018. Since 2019, ADC drugs have ushered in a concentrated period of marketing, and a total of 10 drugs have been approved so far. From the perspective of indications, the distribution of hematological tumors and solid tumors in the marketed drugs is relatively even, 8 are used for the treatment of solid tumors, and 7 are used for hematological tumors. Solid tumors are mainly concentrated in breast cancer and urothelial carcinoma.
2. Global Market Size
The ADC drug market is growing strongly and has broad prospects for development. According to relevant statistics, the global ADC drug market reached US$5.31 billion in 2021, an increase of 87.5% over 2019. And in 2022, the total sales of these ADC drugs are nearly $7 billion. According to Natrue's market forecast, the global ADC drug market will reach US$16.4 billion in 2026, and the market will maintain rapid growth.
Kadcyla and Adcetris have obvious advantages, while Enhertu has the greatest market potential. In terms of individual drug sales, Kadcyla, a second-generation drug, ranked first globally in 2021 with $2.178 billion in revenue, making it the most commercially successful ADC drug to date. Adcetris ranked second with sales of $1.306 billion. These two drugs have been on the market earlier, occupying absolute market advantages. The sales of star drug Enhertu exceeded 400 million US dollars, ranking third. According to the relevant estimation published by Nature, Enhertu sales will exceed 6 billion yuan in 2026 to jump to the first place by virtue of its remarkable clinical efficacy and rich indications.
Prospects For A New Generation of ADC Drugs
1. Finding new targets and expanding indications has become an important trend
The current global marketed drugs and research pipelines are mainly concentrated on mature targets such as HER2 and CD22, and the competition for target homogeneity is relatively serious, especially the launch of the blockbuster drug Enhertu. The research and development of new drugs has brought great pressure, and the search for new targets has become the research and development focus of pharmaceutical companies. At present, pipelines of emerging targets such as HER3, TIM1, and SEZ6 have emerged, and the indications have also been expanded to non-small cell lung cancer, kidney cancer, gastric cancer, ovarian cancer, metastatic rectal cancer, and other types of cancer.
2. Bispecific antibody-drug conjugates become a new direction of exploration
Bispecific antibodies can simultaneously recognize two epitopes of a target or two different targets, and their clinical effect is better than that of monoclonal antibodies. The rapid development of bispecific antibody technology has provided a new direction for the development of ADC drugs. Dual-antibody ADC drugs have the dual advantages of dual-antibody and ADC drugs, which may effectively solve the problems of low endocytosis efficiency, off-target toxicity and side effects and drug resistance faced by ADC drugs.
3. New drug conjugates (XDC) have broad development space
With the continuous advancement of technology, scientists and R&D companies have put forward more ideas based on the ADC structure, and have developed a variety of new conjugation technology concepts, including peptide drug conjugates (PDC), small molecule-drug conjugates (SMDC), immune-stimulating antibody conjugate (ISAC), antibody-oligonucleotide conjugates (AOC), radionuclide drug conjugates (RDC), antibody fragment-drug conjugates (FDC), aptamer drug conjugates (ApDC), antibody cell drug conjugates (ACC), etc. The indications of these new drugs are no longer limited to tumor treatment, but have also begun to expand to autoimmune diseases, bringing hope to more patients.
Globally, a variety of ADC therapies have been successfully developed, benefiting tens of thousands of cancer patients. The approval of 15 ADC drugs and the excellent clinical performance of multiple ADCs have also attracted more attention to the field, which is very important for this relatively young but highly complex field. The increasing number of ADC drug approvals has stimulated the enthusiasm of researchers for ADC research and development. With the ongoing efforts of researchers in these areas, it is hoped that more ADC drugs with greater efficacy and fewer side effects will be approved and marketed, ultimately having a transformative impact on the treatment of cancer patients.
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