Each year, Nature Biotechnology profiles a company that raised significant early-stage funding in the previous year. Indapta Therapeutics uses a subset of natural killer cells found in healthy donors to boost monoclonal antibodies that fight cancer and autoimmune diseases.
Natural killer (NK) cells are cytotoxic effector cells of the innate immune system and are attractive candidates for immunotherapy due to their ability to generally recognize and kill stressed cells such as tumor cells or virus-infected cells. However, depending on the specific repertoire of inhibitory and activating receptors that bind to their respective ligands on target cells, some NK cells have better killing power than others. Indapta Therapeutics aims to harness the power of a specialized subset of NK cells primed to be super killers.
Stephanie Mandl Credit: Indapta Therapeutics
The company was co-founded in 2017 by Guy DiPierro and Ronald Martel, and is now built on the research of its scientist founders, who are based at Stanford University and the University of California, Davis. The research focuses on a set of NK cells, first described by Sungjin Kim and colleagues1,2,3, that are generated in some people’s bodies after infection with cytomegalovirus (CMV). “CMV infection is very common,” explains Stephanie Mandl, Indapta’s CSO. “In 25% of infected people, a special subset of NK cells is primed in response to CMV and undergoes epigenetic modifications that produce a very specialized and stable phenotype.”
These NK cells, termed “g-NK” cells, have several characteristics that make them ideal candidates for development into cell therapies. First, they can be produced as an off-the-shelf therapy, in contrast to approved chimeric antigen receptor (CAR)-T cell therapies for hematological cancers, which require a time-consuming and costly manufacturing process using cells taken from individual patients. Second, g-NK cells have a distinct receptor repertoire compared to conventional NK cells, making them highly suitable for combination with monoclonal antibody therapies targeting proteins expressed on pathogenic cells.
The main difference is the lack of expression of FcεRIγ, an adaptor protein that controls the signaling of the activating receptor CD16 on NK cells. In conventional NK cells, CD16 recognizes antibody-coated target cells and triggers antibody-dependent cellular cytotoxicity (ADCC), an immune response that releases cytotoxic factors to eliminate target cells. The lack of FcεRIγ on g-NK cells alters the activity of CD16, resulting in the release of more cancer-killing factors after interaction with antibody-coated target cells, dramatically enhancing ADCC.
To take advantage of this property, Indapta aims to combine g-NK cells with monoclonal antibodies. Many therapeutic antibodies target cancer cells via ADCC and rely on endogenous NK cells to trigger this response. However, NK cell function is often impaired in cancer patients. Combination therapy with g-NK cells could overcome this issue. [FDA approved] “When you combine monoclonal antibodies with adoptive NK cell therapy, you have NK cells that can mediate ADCC,” Mandl says.
Indapta has raised $60 million in Series A funding and is currently testing its first g-NK cell product, IDP-023. This Phase I/II clinical trial in patients with advanced blood cancers will first confirm the safety of IDP-23 with and without interleukin-2, an approved cancer immunotherapy. Depending on the patient’s type of blood cancer, it will be combined with either daratumumab, a therapeutic antibody that targets CD38 on myeloma cells and is approved to treat multiple myeloma, or rituximab, which targets CD20 on B cells and is approved to treat non-Hodgkin’s lymphoma. The U.S. Food and Drug Administration recently granted IDP-23 fast track designation, a process that helps get drugs to patients more quickly. “This is a recognition of the potential of this therapy to address a significant unmet medical need,” Mandl says. Early observations from one multiple myeloma patient in the trial who was treated with g-NK cells alone were promising: “The patient had a very good partial response, which we’re very excited about.”
g-NK cells have the potential to be used in a variety of fields, including anti-cancer treatment. [NK cell therapy] “This is exactly where the field is heading,” says Karl-Johan Malmberg, an immunologist working on competing platforms at the University of Oslo and the Karolinska Institutet. g-NK cells can be easily combined with different monoclonal antibodies, antibody-drug conjugates, or other innate immune system engagers to vary target specificity. “This allows us to rapidly expand into different clinical indications,” Mandl continues. On cancer, Indopta hopes to one day branch out into solid tumors.
However, Indapta will initially focus on expanding its pipeline targeting autoimmune diseases. The rationale for this decision is the fact that g-NK cells are negative for the inhibitory receptor NKG2A, while expressing high levels of the activating receptor NKG2C. Both NKG2A and NKG2C bind to the non-classical HLA class I molecule HLA-E on target cells, which is expressed at low levels on most cells. In conventional NK cells, the strong NKG2A–HLA-E interaction inhibits unwanted targeting to healthy tissues. However, many diseased cells upregulate the expression of HLA-E to avoid immune surveillance. g-NK cells can counter this adaptation by prioritizing the activating NKG2C–HLA-E interaction. A recent study published in Cell4 showed that a subset of NK cells with high expression of NKG2C can kill autoreactive B and T cells. The potency of this NK cell response has been associated with a reduced risk of developing multiple sclerosis (MS) in healthy people and has generally been weaker in MS patients. “The phenotype and origin of these cells overlaps highly with our cell products,” Mandl says. She thinks Indapta’s cells may be an ideal treatment for MS patients. g-NK cells could be combined with therapeutic antibodies to eliminate autoreactive B cells while simultaneously directly targeting NKG2C–HLA-E to eliminate autoreactive T cells expressing HLA-E, addressing a key aspect of MS that “CAR T-cell therapy cannot address.” Unlike the specific receptor repertoire of g-NK cells that can perform this dual action, CAR T cells are engineered to express a single receptor that recognizes an antigen present on the target cell.
Malmberg believes that “it’s a clever idea to take advantage of both the ADCC ability and the ability to target HLA-E positive cells” for the treatment of autoimmune diseases. He predicts that the durability that is an issue with NK cell-based cancer therapy will be less of an issue in the case of autoimmune diseases. Furthermore, Indapta claims that g-NK cells can effectively recognize virus-infected cells, which could help “eliminate latent viral reservoirs.” [of Epstein-Barr virus] “It could potentially lead to relapses of autoimmune disease,” Mandl said. Indapta is preparing to submit two Investigational New Drug applications to explore the potential of its g-NK cell therapy in MS and autoimmune kidney disease.
Because g-NK cells don’t require engineering to insert genes that enhance their performance, potential advantages include reduced cost, easier regulatory approval, and no risk of malignancy caused by vector integration. But adding a CAR that targets a specific antigen could still be useful in some situations, Malmberg said. “For example, if you have an HLA-E-negative target, these cells work very well based on the CAR.”
In addition to enhanced ADCC and targeting of HLA-E positive cells, Malmberg is excited about another feature that makes g-NK cells such powerful killers. Work on his platform has shown that g-NK cells (which he calls ADAPT-NK cells) also have a unique inhibitory killer immunoglobulin-like receptor (KIR) repertoire, expressing only one KIR. KIRs are another major class of inhibitory receptors that bind to self-HLA class I ligands to dampen NK cell responses against normal tissues. The fact that g-NK cells express only one KIR can be exploited to overcome this inhibitory effect against tumor cells. A 2022 study from his lab5 showed that mismatching single KIR+ ADAPT-NK cells with tumor cells lacking the corresponding KIR ligand increased alloreactivity against leukemia.
A major hurdle in developing these cells into therapeutic products is manufacturing. Compared to NK cells, g-NK cells are difficult to grow due to their lower proliferation capacity. Indapta does not disclose its manufacturing process, but Mandl says that “we have spent a lot of time and effort optimizing the manufacturing process and overcoming the hurdles of scale-up.” If successfully brought to market, the broad therapeutic utility of g-NK cells could fulfill the promise of off-the-shelf NK cell therapy, providing a safe and effective treatment for a wide range of patients.
