Antibody Drug Conjugates: "Biological Missiles" For Targeting Cancer Therapy
Antibody-drug conjugates (ADCs) usually consist of monoclonal antibodies (mAbs) covalently linked to cytotoxic drugs via chemical linkers. With high specific targeting ability and strong killing effect, it has achieved precise and efficient removal of cancer cells, and has become one of the hot spots in the development of anticancer drugs.
In 2000, the FDA first approved the ADC drug Mylotarg (gemtuzumab ozogamicin) for adult acute myeloid leukemia (AML), marking the beginning of the era of ADC targeted cancer therapy. At present, 15 ADCs have been approved globally for hematological malignancies and solid tumors. In addition, more than 100 ADC drug candidates are currently under clinical investigation. The new class of cancer drugs, known as 'biological missiles,' usher in a new era of targeted cancer therapy.
The Main Components of ADCs
ADCs consist of antibodies, cytotoxic payloads, and chemical linkers. An ideal ADC drug remains stable in blood circulation, accurately reaches the therapeutic target, and eventually releases the cytotoxic payload in the vicinity of the target (such as cancer cells). Each element will affect the final efficacy and safety of ADC, and usually the development of ADC needs to consider all these key components, including target antigen, antibody, cytotoxic load, choice of linker as the method of conjugation.
Selection of ADC Target Antigens
Currently, the target antigens of approved ADC drugs are typically specific proteins that are overexpressed in cancer cells, including HER2, trop2, nectin4, and EGFR in solid tumors, and CD19, CD22, CD33, CD30, BCMA, and CD79b in hematological malignancies. Driven by basic research in oncology and immunology, the selection of ADC target antigens has gradually expanded from traditional tumor cell antigens to targets in the tumor microenvironment, such as stroma and blood vessels.
Emerging evidence in preclinical and clinical settings suggests that components of the neovasculature, subendothelial extracellular matrix, and tumor stroma may be valuable target antigens for ADC drug development. For example, matrix-targeting ADC drugs have the potential to cause cancer cell death by reducing the concentration of growth factors produced by matrix-resident cells. Since the survival of cancer cells depends on angiogenesis and stromal factors, ADCs may have broader efficacy against such tissues. In addition, the genomes of these cells are more stable than those of cancer cells, which could be a promising means to reduce the likelihood of mutations causing drug resistance.
Representative Small Molecule Payloads in ADC Drugs
After intravenous administration, about 2% of ADCs reach the target tumor site and need to be highly effective as payloads in ADCs (IC50s need to be in the nanomolar and picomolar classes). In addition, these compounds should remain stable under physiological conditions and have functional groups available to conjugate with antibodies. At present, the cytotoxic payloads of ADCs mainly include powerful tubulin inhibitors, DNA damage agents and immunomodulators.
The Mechanism of Action of ADC
ADC synergistically exerts a 'specific' targeting effect and an 'efficient' killing effect on cancer cells. These drugs are like a precision-guided 'biological missile', which can precisely destroy cancer cells, improve the treatment window and treatment time, and reduce off-target side effects. Once the ADC mAb binds to the target antigen specifically expressed by cancer cells, the ADC is endocytosed/internalized to form early endosomes, which then mature into late endosomes and finally fuse with lysosomes. Cytotoxic payloads are ultimately released chemically or enzymatically in lysosomes, leading to apoptosis or death by targeting DNA or microtubules. When the released payload is permeable or transmembrane, it may also induce a bystander effect to enhance the efficacy of the ADC.
In addition, the anticancer activity of ADC is also involved in the ADCC, ADCP, and CDC effects. The Fab segment of some ADC antibodies binds to epitopes of virus-infected cells or tumor cells, while the FC segment binds to FCR on the surface of killer cells (NK cells, macrophages, etc.) to mediate direct killing. In addition, the antibody component of ADC specifically binds to epitope antigens of cancer cells and inhibits downstream signal transduction of the antigen receptor. Trastuzumab, such as T-DM1, can bind to HER2 receptor of cancer cells, block heterodimer formation between HER2 and HER1, HER3 or HER4, inhibit signal transduction pathways for cell survival and proliferation (such as PI3K or MAPK), and induce cell apoptosis.
For decades, academic and industry efforts have successfully developed a variety of ADC therapies that have benefited thousands of cancer patients. The launch of 15 ADC drugs and the exciting clinical presentations of other ADC drug candidates have also attracted more attention from the field, which is important for this relatively young but highly complex field. It is critical to establish appropriate methods to evaluate the effects of various components of ADC in vitro and in vivo. Identifying and validating new antigens/antibodies, developing new payloads with optimal toxicity, and designing new linkers to balance stability and payload release are critical to the development of next-generation ADC drugs. With the continuous efforts of researchers in these fields, it is not hard to imagine that there will be more surprises in the future for ADC in cancer targeted therapy.
In the future, ADC drugs will have a huge potential in the anti-cancer market. As a worldwide leader of PEG linker supplier, Biopharma PEG offers a wide array of different ADC Linkers to empower our customer's advanced research.
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