Cancer stem cells and normal tissue stem cells share many surface marker proteins, making the cancer stem cell a difficult therapeutic target.
One solution may be an antibody-drug conjugate combining a cytotoxic drug with an antibody that recognizes surface antigens enriched on cancer cells. Such a therapy would bind, internalize, and deliver the cytotoxic drug preferentially to the cancer cells.
Scientists have hypothesized that targeting the intestinal stem-cell surface leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5)—a well-characterized tissue stem cell and cancer stem cell marker—with an antibody conjugated to a distinct cytotoxic drug could allow for selective cancer stem cell targeting.
Their research in animal models, published in Science Translational Medicine (2015;7:314ra186), showed an antibody-drug conjugate targeting LGR5 in tumors could be safe and efficacious. But they emphasized that linker and drug selection are critical to spare normal tissue.
“Our data provide clear evidence that appropriately designed antibody-drug conjugates can be a successful strategy for targeting cancer stem cells despite target expression on normal stem cells,” the authors wrote.
The findings are consistent with known properties of the antibody-drug conjugates and the biology of LGR5, the paper's first author Melissa Junttila, PhD, Senior Scientist in Translational Oncology at Genentech, said in an email. An antibody-drug conjugate could provide a robust and durable anti-tumor response by eliminating the cells hypothesized to be responsible for maintenance and growth of tumors, she explained.
“We demonstrated that a stem cell antigen common among both normal and tumor tissues can be selectively targeted to render an anti-tumor response in the absence of damage to normal tissue homeostasis that relies on the same marker-positive cell population,” Junttila said.
Comparing Two Versions
The researchers developed two antibody-drug conjugates using the same anti-LGR5 antibody with two distinct toxic agents: one with the microtubule inhibitor monomethyl auristatin E (MMAE), a synthetic antineoplastic agent; and another with the topoisomerase-inhibiting anthracycline PNU159682. MMAE is used in brentuximab vedotin, the recently approved anti-CD30 antibody-drug conjugate for the treatment of relapsed Hodgkin's lymphoma (OT 9/10/15 issue).
Treatment of mouse xenograft models with either antibody-drug conjugate reduced tumor size more than controls, but the conjugate containing MMAE was less toxic.
The differences in toxicity profiles between the molecules is consistent with multiple factors underlying tissue and cancer susceptibility to antibody-drug conjugate-mediated killing, Junttila said. These factors could include the mechanism of action for the drug conjugate, antigen expression level on targeted cell types, sensitivity of the targeted cell, and sensitivity of bystander cells to the free drug.
Furthermore, the MMAE-containing monoclonal antibody decreased tumor size and proliferation, which translated into improved survival in a genetically engineered model of intestinal tumorigenesis.
Junttila noted that the reason for the lack of gut toxicity with MMAE conjugate could be that the elimination of intestinal LGR5+ cells within homeostatic tissue is well-tolerated.
“Previous genetic experiments support this concept, because LGR5-positive cell depletion by a knock-in genetic approach that allowed for the targeted elimination of LGR5-positive cells in vivo did not demonstrate adverse effects on gut homeostasis,” she said. “With this system, it was shown that transient removal of LGR5-positive cells left the gut phenotypically unaffected, suggesting that LGR5-positive cells are dispensable and LGR5-negative cell populations participate in gut maintenance.”
Translating the Findings in Human Tumors
In the mouse, LGR5 has been reported to identify stem cells in many tissues and even function as the cell of origin for tumors in those tissues, which would make those tumor types ideal candidates, Junttila said—but the fidelity of those findings with the human tumors remains to be established.
“We plan to further explore ways to increase the efficacy of antibody-drug conjugates, including exploring target biology such as stem cells and drugs that are selective for tumor over normal tissue,” she said. “These data demonstrate that antibody-drug conjugates can be leveraged to exploit differences between normal and cancer stem cells to successfully target gastrointestinal cancers.”