Food and Drug Administration (FDA) firstly approved ADC drug, Mylotarg ® (gemtuzumab ozogamicin), for adults with acute myeloid leukemia (AML), which marked the beginning of ADC era of cancer targeted therapy. Moreover, owing to the conjugation to a large hydrophilic antibody, the antigen-independent uptake of cytotoxic payload in those antigen-negative cells is limited, contributing to widening therapeutic index. 18 ADC consists of a tumor targeting mAbs conjugated to a cytotoxic payload through a sophisticatedly designed chemical linker, enabling the ability of precise targeting and potent effectiveness simultaneously. 17 Hence, a novel concept, known as antibody–drug conjugate (ADC), was conceived to bridge the gap between the mAb and cytotoxic drug for the improvement of therapeutic window. The emergency of mAbs has changed the paradigm of cancer therapy through precise targeting tumor surface antigens, however, treatment using mAbs alone is often insufficient, potentially due to less satisfactory lethality against cancer cells compared to chemotherapy. 12 In recent decades, an increasing number of mAbs, such as avastin, trastuzumab, rituximab, and cetuximab, have been received approval worldwide for treatment of various solid tumors and hematological cancers. 10, 11 Specific expression of these antigens provides the possibility of precision tumor targeting via monoclonal antibodies (mAbs), and this field was advanced greatly after the development of hybridoma technology since 1975. One of the plausible ways is to identify some specifically overexpressed antigens to distinguish cancer cells from health cells, such as HER2 (human epidermal growth factor receptor 2) on the breast cancer and CD20 (cluster of differentiate 20) on the B cell lymphoma. 9 Theoretically, these compounds should be effective in killing cancer cells, but harmless to normal cells. 8 To address this issue, scientists have been working on the development of novel cancer therapeutics with higher targeting ability.Īs early as the beginning of 20th century, Paul Ehrlich first proposed the concept of “magic bullets” and postulate that some compounds could directly access to some desired targets in cell to cure diseases. 3, 4, 5, 6, 7 Most of these chemotherapy agents, however, show low therapeutic index, where severe side effects are generally attributed to non-specific drug exposure to off-target tissues. 2 These cytotoxic agents include analogs of DNA bases (5-fluorouracil and 8-azaguanine), DNA interacting agents (cisplatin and actinomycin D), antimetabolites (aminopterin and methotrexate), and tubulin inhibitors (paclitaxel and vincristine derivatives), etc. 1 Cytotoxic agents based chemotherapy has been the main approach for the treatment of a wide range of cancers for decades. Moreover, we also reviewed the approved ADCs and other promising candidates in phase-3 clinical trials and discuss the current challenges and future perspectives for the development of next generations, which provide insights for the research and development of novel cancer therapeutics using ADCs.Ĭancer has become the second greatest global health threat, accounting for approximately 10.0 million deaths from cancer occurred in 2020. Herein, we conducted a review of the history and general mechanism of action of ADCs, and then briefly discussed the molecular aspects of key components of ADCs and the mechanisms by which these key factors influence the activities of ADCs. This kind of new anti-cancer drugs, known as “biological missiles”, is leading a new era of targeted cancer therapy. Moreover, over 100 ADC candidates have been investigated in clinical stages at present. Since the first ADC, Mylotarg ® (gemtuzumab ozogamicin), was approved in 2000 by the US Food and Drug Administration (FDA), there have been 14 ADCs received market approval so far worldwide. It combines both the advantages of highly specific targeting ability and highly potent killing effect to achieve accurate and efficient elimination of cancer cells, which has become one of the hotspots for the research and development of anticancer drugs. Antibody–drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker.
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