Abstract
Antibody-drug conjugates (ADCs) combine the tumor selectivity of antibodies with the potency of cytotoxic small molecules thereby constituting antibody-mediated chemotherapy. As this inherently limits the adverse effects of the chemotherapeutic, such approaches are heavily pursued by pharma and biotech companies and have resulted in four FDA (Food and Drug Administration)-approved ADCs. However, as with other cancer therapies, durable responses are limited by the fact that under cell stress exerted by these drugs, tumors can acquire mechanisms of escape. Resistance can develop against the antibody component of ADCs by down-regulation/mutation of the targeted cell surface antigen or against payload toxicity by up-regulation of drug efflux transporters. Unique resistance mechanisms specific for the mode of action of ADCs have also emerged, like altered internalization or cell surface recycling of the targeted tumor antigen, changes in the intracellular routing or processing of ADCs, and impaired release of the toxic payload into the cytosol. These evasive changes are tailored to the specific nature and interplay of the three ADC constituents: the antibody, the linker, and the payload. Hence, they do not necessarily endow broad resistance to ADC therapy. This review summarizes preclinical and clinical findings that shed light on the mechanisms of acquired resistance to ADC therapies.
Highlights
The basic principle of antibody-drug conjugates (ADCs) is to enhance the tumor selectivity of cancer treatment with highly cytotoxic small molecules by covalently linking them to antibody molecules directed against tumor-specific cell surface antigens
In 2011, Brentuximab vedotin (BV, AdcetrisTM) was FDA-approved for the treatment of two blood cancer indications: in Hodgkin’s lymphoma (HL) for patients that have failed an autologous stem cell transplant (ASCT) and in systemic anaplastic large cell lymphoma for patients that have relapsed after multi-agent chemotherapy
Such modified trastuzumab-based ADCs have only been tested in a preclinical setting, and it is unclear, how much cardiotoxicity they might cause in patients
Summary
The basic principle of antibody-drug conjugates (ADCs) is to enhance the tumor selectivity of cancer treatment with highly cytotoxic small molecules by covalently linking them to antibody molecules directed against tumor-specific cell surface antigens. The former class is represented by auristatin analogs, maytansinoids, and tubulysins, all of which inherently only kill rapidly dividing cells by inducing mitotic arrest While this property limits off-target toxicities in non-dividing normal cells, it allows tumor stem cells to escape from treatment effects. PBDs, naturally occurring in Actinomyces bacteria, are DNA alkylating compounds that site- cross-link DNA without distorting its double helix structure Besides these two broad classes of payload agents, a limited number of ADC programs alternatively use analogs of the topoisomerase. We discuss challenges and available options for overcoming the emergence of acquired resistance to ADC therapy
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