Understanding ADCs: A Comprehensive Guide

Introduction

Antibody-Drug Conjugates (ADCs) are targeted therapies that consist of antibodies, linkers, and cytotoxic drugs, using monoclonal antibodies as carriers to efficiently deliver cytotoxic drugs to target tumor cells in a targeted manner, combining the powerful killing effect of traditional chemotherapy with the tumor-targeting capability of antibody drugs.

An ideal ADC maintains stability in the bloodstream, accurately reaches the treatment target, and ultimately releases its cytotoxic payload near the target (such as cancer cells). To achieve the desired efficacy and safety of ADCs, five core factors must be comprehensively considered when constructing ADCs: target, antibody, linker, toxin, and conjugation method.

Understanding ADCs: A Comprehensive Guide

Figure 1. Structure and Characteristics of ADCs^[1]

The mechanism of ADC action begins with the binding to target cells; the target antigens expressed on tumor cells guide ADCs in recognizing tumor cells. Additionally, after binding to the antigen, ADCs must be able to undergo endocytosis, be transported within the tumor cell, and be degraded. Therefore, choosing the appropriate target is one of the primary considerations for ADCs.

Target Characteristics

Ideal targets should possess the following characteristics:

(1) Strong tissue specificity: To reduce off-target toxicity, the targeted antigen should be expressed only or primarily in tumor cells and have low or no expression in normal tissues. For example, in some tumors, HER2 expression can be approximately 100 times higher than in normal cells;

(2) High antigen stability: To avoid reduced tumor targeting and safety issues, the targeted antigen should be a surface (or extracellular) antigen, not an intracellular one, and the target antigen should be non-secretory to avoid recognition by the circulatory system;

(3) Efficient antigen internalization: The ideal target antigen should be able to internalize upon binding with the corresponding antibody, allowing the ADC to enter the cancer cell and release its cytotoxic payload through appropriate intracellular transport pathways.

Currently approved ADCs target specific proteins that are overexpressed in cancer cells, including HER2, Trop2, Nectin4, and EGFR in solid tumors, as well as CD19, CD22, CD33, CD30, BCMA, and CD79b in hematological malignancies. Driven by advancements in oncology and immunology research, the selection of ADC target antigens has gradually expanded from traditional tumor cell antigens to targets within the tumor microenvironment (such as in the stroma and vascular system).

Figure 2. Selection of ADC Targets (Tumor Cells and Tumor Microenvironment)^[1]

Approved ADC Targets

Since the first ADC drug Mylotarg^® (gemtuzumab ozogamicin) was approved by the FDA in 2000, as of 2024, there are currently 14 ADC drugs approved worldwide for hematological malignancies and solid tumors. These 14 ADC drugs correspond to 12 targets, which are HER2, CD22, BCMA, CD33, CD30, CD79b, Nectin-4, EGFR, CD19, Tissue Factor (TF), FRα, and Trop2.

Table 1. Approved ADC Drug Targets^[1,2]

Development Status of ADC Targets

Statistics show that there are over 800 ADC drugs in various stages of development globally, with popular ADC targets including HER2, Trop2, EGFR, c-Met, B7-H3, HER3, Nectin-4, CLDN18.2, and PDL1.

Figure 3. Distribution of ADC Targets Under Development Globally (Top 20)^[2]

Common ADC Targets in Lung Cancer

The exploration of ADCs in lung cancer primarily targets HER2, HER3, Trop2, MET, CEACAM5, and B7-H3 (Figure 4), demonstrating significant application potential.

Figure 4. Overview of ADC Targets in Lung Cancer^[3]

1. HER2 Target

HER2 is a receptor tyrosine kinase (RTK) considered a therapeutic target for non-small cell lung cancer (NSCLC). Due to the difficulty of HER2 in internalization and degradation compared to other HER family members, which exhibit higher receptor turnover, it can remain activated on the cell membrane for extended periods, representing an ideal target for ADC development theory.

2. HER3 Target

HER3 is another member of the RTK HER family, commonly expressed in NSCLC (up to 83%). HER3 heterodimerization is a mechanism of resistance to EGFR tyrosine kinase inhibitors (TKIs), functioning by enhancing HER3-dependent oncogenic signaling activation.

3. Trop2 Target

Trop2 is a transmembrane glycoprotein of the epithelial cell adhesion molecule (EpCAM) family, expressed in most tumors but occasionally in normal tissues.

4. CEACAM5 Target

Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are a family of cell surface glycoproteins. CEACAM5 is selectively expressed in several tumor types, including lung cancer.

5. MET Target

MET is the tyrosine kinase receptor for hepatocyte growth factor, with approximately 30%-50% overexpression in NSCLC, while MET amplification (1.5%) or MET exon 14 skipping mutations (3%) are major oncogenic drivers.

6. B7-H3 Target

B7-H3 (also known as CD276) is an important immune checkpoint molecule in the B7 family of proteins, with an unclear ligand, and is highly expressed in cancer cells.

In the field of lung cancer, besides the aforementioned targets, other targets such as EGFR, AXL, and PVRL4 are also under clinical development.

Table 2. Summary of ADC Drug Targets Under Clinical Development in Lung Cancer^[3]

Conclusion

In summary, the competition in the ADC field is becoming increasingly intense, with serious issues of target layout homogeneity. Most targets are in the clinical efficacy verification stage. How to optimize target selection from different dimensions such as technology and indications, and differentiate target advantages, will be the direction for future exploration.

References:

[1] Fu Z, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93

[2] https://www.pharmcube.com/ (Pharmaceutical Cube)

[3] Passaro A, Jänne PA, Peters S. Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies. J Clin Oncol. 2023 Jul 20;41(21):3747-3761. doi: 10.1200/JCO.23.00013. Epub 2023 May 24.

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