by There were no deaths. 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. In addition, we discuss novel ADC strategies of interest in lung cancer, including non-cytotoxic payloads, such as immunomodulatory and anti-apoptotic agents. Subject terms: Drug development, Targeted therapies Introduction Antibody-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 lung cancer, the treatment paradigm has shifted dramatically in recent years, and now Geniposide incorporates targeted therapy, immunotherapy, and systemic chemotherapy, Geniposide and ADCs are now joining the list as potential options for lung cancer patients. ADCs are unique in offering Geniposide 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. 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. 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 linker1,2. To date, twelve ADCs have been granted FDA approval in oncology (Table ?(Table1),1), and with nine of these approved since 2017, the pace of development of this class is only accelerating. Table 1 FDA-approved antibody-drug conjugates (ADCs) available in the clinic. acute myeloid leukemia, B-cell acute lymphoblastic leukemia, B-cell maturation antigen, Hodgkin lymphoma, drug-to-antibody ratio, diffuse large B-cell lymphoma, monoclonal antibody, mycosis fungoides, monomethyl auristatin E, monomethyl auristatin F, anaplastic large cell lymphoma, peripheral T-cell lymphoma, pyrrolobenzodiazepine, topoisomerase I, tumor-associated calcium signal transducer 2. **Used as monotherapy or as a combination strategy with cytarabine and daunorubicin. #Used (1) in combination with doxorubicin, vinblastine, and PR52B dacarbazine (AVD) for newly diagnosed classical HL, (2) as a combination strategy with cyclophosphamide, doxorubicin, and prednisone (CHP) for systemic anaplastic large cell Geniposide lymphomas or (3) CD30+ Peripheral T-cell lymphoma. ?Used as a combination strategy together with rituximab and bendamustine. In this review, we discuss the structure and Geniposide mechanism of action of ADCs, including insights from pre-clinical work; we explore the activity in lung cancer and summarize the recent progress of ADCs in the clinic (Table ?(Table2),2), describe current challenges and toxicity profiles of these compounds; finally, we explore potential combination strategies and other strategies designed to enhance ADC potency and overcome resistance. Table 2 Summary of current key antibody-drug conjugate (ADC) clinical data in metastatic NSCLC. antibody-drug conjugate, complete response, disease control rate, duration of response, not estimable, non-small cell lung cancer, objective response rate, overall survival, progressive disease, progression-free survival, partial response, stable disease. Structure 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 undertaken3,4. It has taken over fifty years of research for the initial promise to.
