Acquired Resistance to Antibody-Drug Conjugates

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.

CRISPR-based screens uncover determinants of immunotherapy response in Multiple Myeloma

“…Immunotherapy agents such as antibody drug conjugates (ADC) are sensitive to changes in expression of target antigen (25). We developed an ADC targeting BCMA, HDP101 (26-28) that has proven efficacy in MM cell lines at sub-nanomolar concentrations.…”

A Novel Antibody-Drug Conjugate (ADC) Delivering a DNA Mono-Alkylating Payload to Chondroitin Sulfate Proteoglycan (CSPG4)-Expressing Melanoma

“…These findings may be significant, since resistance can develop against the antibody or the payload components of the ADC by antigen down-regulation or mutation, or by upregulation of drug efflux transporters, respectively. Resistance has been observed with multiple ADCs in clinical use [2] which has restricted efficacy. For instance, gemtuzumab ozogamicin has been associated with multidrug resistance (MDR) mechanisms [46].…”

“…For instance, gemtuzumab ozogamicin has been associated with multidrug resistance (MDR) mechanisms [46]. Resistance mechanisms towards brentuximab vedotin have been investigated, since more than a third of treated patients that initially achieve a complete response, relapsed and died within five years of treatment [2]. CD30 down-regulation, MMAE resistance, and upregulation of the MDR1 drug exporter protein have all been shown to be associated with resistance to brentuximab vedotin [47].…”

“…Antibody-drug conjugates (ADCs) deliver highly cytotoxic payloads directly to cancer cells by linking the payload to a monoclonal antibody that recognizes a tumor antigen [1]. The design of an ADC entails selection of an appropriate cell surface target antigen, and subsequent generation of an antibody capable of internalizing in the cancer cells followed by release of the payload [2]. Ideally, the payload should be able to kill non-dividing as well as dividing cancer cells, and released only at the tumor site, thus sparing healthy tissue from exposure to its toxic effects [3].…”

Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

“…Resistance to the ADC treatment is another factor that is related to the payload selection. Cancer cells may acquire the overexpression of ABC transporters for the efflux of chemotherapeutic drugs, most notably P-glycoprotein 1 (Pgp, also known as ABCB1, MDR1 or multidrug resistance 1), and many ADC payload molecules are substrates for these transporters that have a broad substrate specificity for hydrophobic molecules [124]. For example, the acquired resistance of HL-60 cells chronically exposed to gemtuzumab ozogamicin was attributed the induction of overexpression of MDR1 [125].…”