Drugmakers, including the genetic testing company 23andMe, are using novel approaches to stimulate NK cells’ intrinsic ability to recognize and kill tumor cells.
As their name suggests, natural killer (NK) cells intrinsically recognize and kill stressed cells, such as cancer cells. NK cells are not a new approach to treating cancer, but a novel class of antibodies is giving them a leg up in the fight, and drugmakers, including 23andMe and Innate Pharma, are leveraging this approach to develop cell therapies for a range of cancers.
NK cells have a number of receptors that recognize specific stress ligands present on cancer cells, Lewis Lanier, a professor in microbiology and immunology at the University of California, San Francisco, told BioSpace. Antibody-based therapies promote NK cells’ anti-tumor activity by manipulating the receptor-ligand interactions and help NK cells to infiltrate the tumor site.
While their approaches are different, both 23andMe and Innate are developing such therapies to activate the intrinsic ability of NK cells to recognize and kill tumor cells.
Uncovering a Novel I-O Target
Best known as a direct-to-consumer genetic testing company, 23andMe was founded in April 2006. Since then, the company has developed one of the largest databases of consumer genetic data.
Jennifer Low, head of therapeutics development at 23andMe, told BioSpace that 80% of customers have consented to provide their health data, “including health experiences, family histories, their activities and medical records.”
The company’s genetic database comprises genotypic and phenotypic data from 15 million people, including information about genetic variants, which informs its in-house drug discovery programs as well as programs initiated through collaborations, Low said. Specifically, the database contains information about parts of the genome that might provide insight for the development of novel immuno-oncology therapies, she noted.
“The real problem with developing cancer therapies is that you need a target that’s not expressed on healthy tissues,” Lanier said. “If people can look through these massive datasets and find evidence for the overexpression of certain tumor ligands, that can be exploited therapeutically.”
Earlier this month at the American Association for Cancer Research’s annual meeting, 23andMe presented data on its two clinical-stage programs. One, an antibody called 23ME-01473, targets soluble ULBP6, a dominant immunosuppressor shed by tumor cells. The novel target, discovered using the company’s genetic and health survey database, is a ligand for NKG2D, an NK cell surface receptor that recognizes a wide array of stress-associated ligands expressed on tumor cells. Tumor cells shed ULBP6 into the tumor microenvironment to bind NKG2D, bypassing recognition by NK cells. Blocking ULBP6-NKG2D binding may thus restore immune cell recognition and killing of cancers, according to 23andMe.
“There is some data suggesting ULBP6 is overexpressed in some tumors,” Lanier said, adding that using an antibody against ULBP6 is a “good strategy.” In addition to targeting the ULBP6-NKG2D interaction, Low said, 23andMe’s investigational antibody also has an Fc-effector-enhanced region capable of engaging NK cells and further enhancing their function.
23andMe initiated a Phase I clinical trial in March 2024 to evaluate the safety and tolerability of 23ME-01473 in patients with advanced solid tumors that have progressed on standard-of-care treatments.
NK Cell Engagers
Biopharma has long recognized the potential of NK cells. Lately in the cell and gene therapy space, NK cell therapies have captured attention. The global NK cell therapy market stood at $92 million in 2022 and is projected to reach $3.1 billion by 2031.
But even short of infusing these natural killers into cancer patients, several companies are looking to harness NK cell biology to fight cancer. In addition to 23andMe, other players in this space include Dragonfly Therapeutics, D2M Biotherapeutics and Innate Pharma.
“Our therapeutic strategies have two main focuses: Unleashing NK cells or stimulating NK cells via NK cell engagers,” Eric Vivier, SVP and chief scientific officer of Innate, told BioSpace.
Innate’s lead asset, IPH6101/SAR443579, being developed in partnership with Sanofi, is an antibody-based NK cell engager directed against NK cell receptors NKp46 and CD16 and against the tumor antigen CD123, which is overexpressed in acute myeloid leukemia (AML). Vivier explained the rationale behind the selection of the two NK cell receptors. “NKp46 is a stably expressed activating receptor found on NK cells,” and CD16 is a receptor for antibodies that also stimulates NK cell function.
Innate and Sanofi kicked off a Phase II dose expansion trial of IPH6101/SAR443579 last week. The companies plan to recruit 126 patients with AML, B-cell acute lymphoblastic leukemia, and high-risk myelodysplasia, among other cancers.
Vivier said NK cell engagers have a possible advantage over T cell engagers as they do not induce a cytokine storm—a severe immune response leading to the excessive release of pro-inflammatory cytokines, organ damage and mortality—common to the latter.
Another candidate, IPH6501 is an NK cell engager that also targets NKp46 and CD16, plus the tumor antigen CD20, and is armed with a variant of interleukin 2 (IL-2). Adding cytokines such as IL-2 to the NK cell engager induces cell proliferation pathways and boosts immune response, Vivier explained.
Lanier agreed. While NK cell engagers draw NK cells from the blood to the tumor, NK cells that make it into tumors get shut down by the immunosuppressive microenvironment, he noted. “Introducing cytokines wakes up NK cells and restores their functionality.”
In preclinical studies, IPH6501 showed “massive infiltration” of NK cells to the tumor and good tumor growth control, Vivier said. Safety and tolerability of the asset is currently being evaluated in a Phase I clinical trial for patients with relapsed/refractory non-Hodgkin’s lymphoma, with initial data expected in 2025.
A 2023 article published in the Journal of Hematology & Oncology posits that T-cell engagers “will likely revolutionize the treatment of hematological malignancies in the short term, as they are considerably more potent than conventional monoclonal antibodies recognizing the same tumor antigens.” Bispecific NK cell engagers offer similar efficacy with milder side effects, the authors note, and trispecific antibodies “raise the game even further.”
“Altogether, these engineered molecules may change the paradigm of treatment for relapsed or refractory hematological malignancies,” the authors write.
Sunitha Chari is a freelance science writer and academic editor based in Toronto. See more of her work at sunithachari.contently.com and reach her at sunithachari.02@gmail.com.
Correction (April 22): This article has been updated from its original version to correct that Eric Vivier is SVP and chief scientific officer of Innate Pharma, not president and CEO. BioSpace regrets the error.
