抗体-药物偶联物(antibody–drug conjugates,ADC )
Antibody–drug conjugates (ADCs) are among the fast- est growing drug classes in oncology. These therapeutic entities are composed of monoclonal antibodies (mAbs) linked to cytotoxic drugs and are designed, in principle, to widen the therapeutic window of those drugs by lim- iting their delivery specifically to cells that express the target antigen of the selected mAb1–4. Emerging evidence indicates that the efficacy of an ADC is dependent upon antibody-specific, linker-specific and payload-specific factors, each of which is a function of complex inter- actions between the ADC and various components of the tumour and the tumour microenvironment (TME)5. Many ADCs have demonstrated impressive activ- ity against treatment-refractory cancers, resulting in approvals in numerous and diverse indications (Table 1); however, their broader use is limited by various chal- lenges, including toxicities, suboptimal predictive bio- markers, unknown clinical value in combination with standard therapies and poorly understood pathways of drug resistance.
Progress in synthetic biochemistry methods, includ- ing in mAb production, linker technology and novel payload discovery, has paved the way for a new gener- ation of ADCs with the potential to improve upon the activity and toxicity profiles of earlier generations of ADCs6. At the time of publication, nine different ADCs have been approved for the treatment of patients with cancer (Table 1), with dozens more at various stages of preclinical and clinical development7. In this Review, we first discuss the historical development of ADCs, how they are constructed and insights from preclinical studies regarding their mechanism of action. We then discuss how these properties manifest clinically, using examples to explore the activity and toxicity profiles of ADCs. Finally, we conclude with potential strategies that could be tested to overcome these barriers and maximize the anticancer efficacy of ADCs in clinical practice.
表1. ADCs currently approved by the US FDA
ADC | | | | | | | | Disease indication (year of approval) | | | | | | | | | | | | | | | | | | R/R sALCL or cHL (2011) R/R pcALCL or CD30+ MF(2017) cHL, sALCL or CD30+PTCL (2018)b | Ado-trastuzumab emtansine (T-DM1) | | | | | | | | Advanced-stage HER2+breast cancer previously treated with trastuzumab and a taxane (2013); early stage HER2+ breast cancer in patients with residual disease after neoadjuvant trastuzumab–taxane-based treatment (2019) | | | | | | | | | | Fam-trastuzumab deruxtecan-nxki (T-DXd) | | | | | | | | Advanced-stage HER2+breast cancer after two or more anti-HER2-based regimens (2019) | | | | | | | | | | Sacituzumab govitecan-hziy | | | | SN-38 (active metabolite of irinotecan) | | | | Advanced-stage, triple-negative breast cancer in the third-line setting or beyond (2020) | | | | | | | | | Advanced-stage urothelial carcinoma, following progression on a PD-1 or PD-L1 inhibitor and platinum-containing chemotherapy (2020) | Belantamab mafodotin-blmf | | | | | | | | R/R multiple myeloma in the fifth-line setting or beyond (2020) |
ADC, antibody–drug conjugate; AML, acute myeloid leukaemia; B-ALL, B cell acute lymphoblastic leukaemia; BCMA, B cell maturation antigen; cHL, classical Hodgkin lymphoma; DAR, drug-to-antibody ratio; DLBCL, diffuse large B cell lymphoma; mAb, monoclonal antibody; MF, mycosis fungoides; MMAE, monomethyl auristatin E; MMAF, monomethyl auristatin F; pcALCL, primary cutaneous anaplastic large cell lymphoma; PTCL, peripheral T cell lymphoma; R/R, relapsed and/or refractory; sALCL, systemic anaplastic large cell lymphoma; TOPO1, topoisomerase I; TROP2, tumour-associated calcium signal transducer 2. aAs a single agent or in combination with daunorubicin and cytarabine. Gemtuzumab ozogamicin was withdrawn from the market in 2010 and re-approved in 2017 for newly diagnosed or R/R CD33-positive AML. bIn combination with cyclophosphamide, doxorubicin and prednisone for newly diagnosed sALCL or CD30+ PTCL and in combination with doxorubicin, vinblastine and dacarbazine for newly diagnosed cHL. cIn combination with bendamustine and rituximab.
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