Targeting LGR5 ⁺ cells with an antibody-drug conjugate for the treatment of colon cancer

Abstract

Cancer stem cells (CSCs) are hypothesized to actively maintain tumors similarly to how their normal counterparts replenish differentiated cell types within tissues, making them an attractive therapeutic target for the treatment of cancer. Because most CSC markers also label normal tissue stem cells, it is unclear how to selectively target them without compromising normal tissue homeostasis. We evaluated a strategy that targets the cell surface leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a well-characterized tissue stem cell and CSC marker, with an antibody conjugated to distinct cytotoxic drugs. One antibody-drug conjugate (ADC) demonstrated potent tumor efficacy and safety in vivo. Furthermore, the ADC decreased tumor size and proliferation, translating to improved survival in a genetically engineered model of intestinal tumorigenesis. These data demonstrate that ADCs can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers.

LGR5-Targeted Antibody–Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence

“…Thus, an LGR5-targeting ADC may not only effectively treat gastrointestinal tumors, but also function to eliminate CSCs. In fact, while this manuscript was in preparation, a report was published further validating the importance and effectiveness of targeting LGR5 for the treatment of colon cancer using different ADCs (44). In summary, our anti-LGR5-mc-vc-PAB-MMAE has demonstrated significant efficacy in gastrointestinal cancer cell lines and in a colon cancer xenograft model, suggesting its potential as a promising new therapeutic to target CSCs, eradicate a LGR5-positive tumors of different tissue types, and prevent recurrence.…”

Highly Potent, Anthracycline-based Antibody–Drug Conjugates Generated by Enzymatic, Site-specific Conjugation

“…PNU-159682 was described to be several orders of magnitude more potent than doxorubicin (34) and has recently shown promise as a payload for ADCs in the context of conventional chemical conjugation (32,33). Indeed, when conjugated to trastuzumab, a significantly increased cytotoxic activity was achieved in comparison with maytansine conjugates and even cells with moderate HER2 expression levels, that were not sensitive to Kadcyla, could efficiently be killed (Figs.…”

“…Finally, alternative payloads with substantially higher potency than microtubuledisrupting agents are being investigated, including pyrrolobenzodiazepine (PBD) dimers (29), enedyenes such as calicheamicin (30), indilino-benzodiazepine (IBD) pseudodimers (termed IGNs; ref. 31), as well as novel anthracylines (32,33).…”

Antibody–Drug Conjugates for Cancer Therapy

“…The importance of payload selection for stem cell targeting was recently reported in the analysis of two ADCs targeting the Lgr5+ colorectal stem cell and putative cancer stem cell marker [44]. An anti-microtubule targeting anti-LGR5–vc-MMAE ADC was effective in vivo, without affecting the homeostasis of the normal intestinal epithelium in the mouse models explored.…”