![]() This feature of certain ADCs is often debated and some pharmacological characteristics, such as a hydrophobic payload or a cleavable linker, appear to play a major role in this phenomen 5. Some payloads exert a bystander effect, where the free drug is released unintentionally from the target tumor cell across the cell membrane following internalization and degradation of the ADC, to kill adjacent tumor cells, including those cells that may not express the target antigen on its cell surface. Each of these three components can differ between different ADCs, which may lead to contrasting pharmacological and clinical properties. Many of the recent next-generation ADCs have impressive activity against treatment-refractory cancers, and while limitations remain, such as toxicities related to treatment, inadequate biomarker selection, and acquired resistance, there is a reason for optimism for this therapeutic approach.Īs a class of drugs, all ADCs are composed of three principal components: an antibody that binds a tumor-associated antigen, a cytotoxic payload, and a linker that connects the two (Fig. It has taken over fifty years of research for the initial promise to come to pass–the approvals of second-generation ADCs brentuximab vedotin (Seattle Genetics, developed in 2011) and trastuzumab emtansine (also known as ado-trastuzumab emtansine or TDM1, developed by Roche in 2013), have paved the way for the current plethora of clinical trials investigating potential ADCs in the clinic. The use of ADCs in animal models was first reported in the 1960s, but it was not until the 1980s that the first clinical trials with ADCs based on mouse immunoglobulin G (IgG) molecules were undertaken 3, 4. ![]() To date, twelve ADCs have been granted FDA approval in oncology (Table 1), and with nine of these approved since 2017, the pace of development of this class is only accelerating. Comprising of three key components, ADCs are the “homing missiles” of modern drug development, and include (1) a monoclonal antibody that binds selectively to an antigen on the tumor cell surface, (2) a cytotoxic drug payload, and (3) a cleavable or non-cleavable linker 1, 2. Thus, ADCs are agents of precision oncology, and using these targeting properties one can greatly enhance the therapeutic index of the attached payload, compounds that would otherwise be too toxic for use. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now incorporates targeted therapy, immunotherapy, and systemic chemotherapy, and ADCs are now joining the list as potential options for lung cancer patients.ĪDCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells that express a pre-defined cell surface target, thereby harnessing the powers of both cytotoxic chemotherapy and targeted therapy. In addition, we discuss novel ADC strategies of interest in lung cancer, including non-cytotoxic payloads, such as immunomodulatory and anti-apoptotic agents.Īntibody-drug conjugates (ADCs) are, arguably, the fastest-growing class of oncology drugs in development, and while not a new concept, the potential to change clinical practice is vast. In this review, we discuss the structure and mechanism of action of ADCs, including insights from pre-clinical work we summarize the ADCs’ recent progress in lung cancer, describe toxicity profiles of ADCs, and explore strategies designed to enhance ADC potency and overcome resistance. Furthermore, several early-phase trials are assessing various novel ADCs, either as monotherapy or in combinations with advanced lung cancer, and more selective and potent ADCs are expected to become therapeutic options in clinic soon. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, currently under evaluation (patritumab deruxtecan, telisotuzumab vedotin). In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. ![]() ![]() By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. ![]()
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