Antibody–drug conjugates (ADCs) consist of a monoclonal antibody (mAb) covalently attached to cytotoxic drugs (warheads or payloads) via chemical linkers. They integrate the specificity of antibodies with the potency of cytotoxic drugs to precisely and efficiently eliminate cancer cells. ADCs have become one of the hotspots for the research and development of anticancer drugs^[1].

An ADC is composed of three essential components: a monoclonal antibody that specifically targets antigens on cancer cells, a chemical linker that connects the antibody to the cytotoxic payload, and a cytotoxic payload that kills the cancer cells upon internalization. Among these, the target antigen selection is of paramount importance in ADC design.

Ideal antigen selection requires^[2][3]:

• a)Tumor-specific expression (with minimal presence in normal tissues).
• b)Cell surface localization (can be recognized by ADC).
• c)Non-secreted nature (avoid antigen shedding into the blood and cause ADC off-target).
• d)Efficient internalization (enables intracellular payload release via proper trafficking pathways).

Figure 1. The core components and mechanism of ADCs^[4].

Hot ADC Target Proteins

HER2 is highly expressed in various cancers, including breast, gastric, lung, and ovarian cancer, making it a key target for ADCs. Several approved treatments targeting HER2 include T-DM1 (Trastuzumab emtansine), DS-8201 (Trastuzumab deruxtecan).

EGFR is frequently mutated or overexpressed in various cancer types, and serves as a therapeutic target for multiple cancer treatments, particularly in lung cancer. The bispecific ADC, BL-B01D1, has demonstrated stronger tumor inhibition capacity compared to monospecific anti-EGFR ADC and anti-HER3 ADC separately.

Claudins (CLDNs) are integral components of tight junction assemblies and exhibit tissue-specific expression patterns and distributions in both normal tissues and malignant tumours. Among all claudins, CLDN18.2 has emerged as the most clinically significant, being selectively overexpressed in various cancers, including gastric, pancreatic, esophageal cancers, etc^[5][6]. Targeted therapies against CLDN18.2 include monoclonal antibodies, bispecific antibodies, ADCs, and CAR-T cell therapies. Notably, over 10 CLDN18.2-directed ADCs are currently in clinical development, including leading candidates CMG901 and SYSA-1801^[7].

Cadherin-17 (CDH17) is an emerging therapeutic target overexpressed in digestive system tumors. CDH17 is a membrane protein expressed along the epithelia tissues of gastrointestinal (GI) tract, primarily in the colon, small intestine, and pancreas at a regulated level in healthy individuals. Overexpression of CDH17 is widely reported in various GI cancers, including CRC, gastric cancer, cholangiocarcinoma, hepatocellular carcinoma, pancreatic cancer, etc. It can be used as a biomarker to predict cancer prognosis and as a target for cancer intervention. ADC candidates targeting CDH17, such as SOT109 and TAVO307 have demonstrated robust tumor-suppression activity in multiple preclinical cancer models^[8].

TROP-2 plays a crucial role in tumor cell proliferation, apoptosis, and invasion. As a prognostic marker, TROP-2 holds significant promise as a broad-spectrum anti-tumor target^[9]. Currently, the ADC drug Sacituzumab govitecan targeting TROP-2 has been approved for the treatment of metastatic triple-negative breast cancer (TNBC).

B7-H3 (CD276) is overexpressed in a variety of cancers. Its elevated levels have been linked to increased cell proliferation and enhanced invasiveness in several cancer types, including pancreatic, breast, colorectal, and prostate cancer. Ifinatamab deruxtecan (I-DXd) is an investigational potential first-in-class B7-H3 directed ADC.

MCE offers a comprehensive portfolio of ADC-related products including ADCs molecules, target antigen proteins, antibodies, cytotoxic payloads, and linkers, to support ADC research and development.

ADC Antibodies