At present, ADC drugs are mainly used in the field of tumors, so antigenic targets are required to be highly expressed in tumor cells but with low or no expression in normal tissues, or only expressed in specific tissue types. This standard is strict enough to make it difficult to find good targets, so other factors need to be considered when selecting targets. It includes the type of cells expressing the antigen, the cycle state of the cells (division or resting phase), the expression level of the target, and the accessibility of the target, and so on. Secondly, the target antigen should exist on the cell surface to facilitate the recognition and internalization of mAb. However, the selection of targets is challenging as the number of antigens on the surface of tumor cells is usually limited, and the internalization process of antigen-antibody complexes is usually inefficient.
Among the ADC drugs on the market, the indication of the following five targets: CD22, CD30, CD33, CD79b, and BCMA is hematoma, while the indication of HER2, Nectin-4, and Trop-2 is solid tumors. With regard to the accessibility of targets, solid tumors have larger hindrances than hematological tumors. The microenvironment of solid tumors and other factors make it difficult for drugs to permeate. At this level, the accessibility of hematological tumors is better, which is the key factor why ADC drugs made a breakthrough in the field of hematological tumors.
In addition to the above several listed products, ADC drugs aimed at CD19, Mesothelin, PSMA, EGFR, Nectin-4, CD56, CD138, CD74, and so on are also hot spots.
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HER2
As a high incidence type of breast cancer, HER2 positive also has a high incidence in bladder cancer and gastric cancer. HER2 has been developed as an important target in the treatment of breast cancer for many years. At present, two kinds of ADC drugs for breast cancer are approved worldwide: Kadcyla and Enhertu. In addition, HER2-ADC drugs have made continuous breakthroughs in the treatment of HER2-expressed cancers, such as breast cancer, gastric cancer, bladder cancer, and colorectal cancer, broadening the scope of application of targeted therapy.
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CDs family
CD antigen has become an important target antigen for hematological tumor therapy, accounting for a large proportion of ADC drugs on the market. From the perspective of targets, some drugs targeting CD30, CD22, CD33, and CD79b have been approved to be put on the market, most of which are indicated for hematomas, such as leukemia, lymphoma, and non-Hodgkin’s lymphoma. Among all targets under study, the drugs targeting CD19, CD56, CD138, and CD37 are promoted clinical trials. Among these targets, CD19 is an ideal target for the treatment of a variety of B-cell malignant tumors. From the perspective of indications, the ADC drugs targeted by the CD family are still concentrated on the development of hematological tumors, and no substantial progress has been observed in solid tumors.
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TROP2
Trop2 is a cell surface protein encoded and expressed by the TACSTD2 gene. Its high expression plays a key role in tumor growth, and is also related to more invasive diseases and poor prognosis. It is a good target for ADC drugs for its high and differential expression. In 2020, the first Trop2-targeted ADC drug, Trodelvy, was quickly approved by FDA for adult patients with metastatic triple negative breast cancer (mT NBC) who had previously received at least two treatments for metastatic diseases. Trodelvy is formed by conjugating humanized IgG1 monoclonal antibody with topoenzyme inhibitor SN-38 to target the cell surface glycoprotein Trop2 expressed in more than 90% of triple negative breast cancer.
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BCMA
BCMA, also known as TNFRSF17, is a member of the TNF-receptor family, which plays an important role in autoimmune diseases and humoral immunity, and has a great relationship with Hodgkin’s lymphoma, multiple myeloma, and other diseases. GSK’s Blenrep is the first ADC drug approved to target BCMA in the world. The approval of Blenrep not only marks the success of BCMA targets in the field of ADC, but also shows that ADC drugs have the potential to treat recurrent or refractory diseases.
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c-Met
C-Met is a membrane surface receptor protein with tyrosine kinase activity. Compared with normal tissues, C-Met has significantly higher expression in tumor tissues. Excessive activation of C-Met signaling pathway is closely related to the occurrence of many kinds of malignant tumors, and ADC targeting C-Met is still in a relatively early stage.
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ROR1
ROR1 is a transmembrane tyrosine kinase receptor which is significantly increased in B-cell chronic lymphoblastic leukemia (CLL), acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma (NHL), myeloid hematological cancer, colon cancer, lung cancer, pancreatic cancer, ovarian cancer, and other cancers, therefore becoming a tumor-specific target.
With the maturity of ADC design technology, many biomedical companies around the world begin to explore the use of ADC in the treatment of diseases other than oncology, including ophthalmology, immunology, anti-infection, and endocrine/metabolism. Most of these ADCs for non-cancer indications are still in the early stage of development, but the proportion is gradually increasing. According to incomplete statistics, in the ADC drugs that treat non-cancer indications, the vast majority of the loads are non-cytotoxic drugs, accounting for 90% of research and development projects. These non-cytotoxic drug loads include immunomodulators, enzymes, as well as innovative treatment models such as antisense oligodeoxynucleotides and siRNA.