Each year, Nature Biotechnology highlights companies that have received sizeable early-stage funding in the previous year. Indapta Therapeutics is using a subset of natural killer cells found in healthy donors to supercharge monoclonal antibodies to fight cancer and autoimmune disease.
Natural killer (NK) cells, the cytotoxic effector cells of the innate immune system, are attractive candidates for immunotherapy because of their ability to generally recognize and kill stressed cells, such as tumor cells and virus-infected cells. However, some NK cells are better killers than others, depending on their specific repertoire of inhibitory and activating receptors that bind to respective ligands on target cells. Indapta Therapeutics aims to harness the power of a subset of specialized NK cells that are primed to be super killers.
Stefanie Mandl
Credit: Indapta Therapeutics
The company was co-founded in 2017 by Guy DiPierro and Ronald Martell and is built on research from scientific founders now based at Stanford University and the University of California, Davis. This work focused on a set of NK cells, originally described by Sungjin Kim and colleagues1,2,3, that are produced in some people after they have been infected with cytomegalovirus (CMV). “CMV infection is very common,” explains Stefanie Mandl, CSO at Indapta: “In 25% of people that get infected, a special subset of NK cells gets primed in response to CMV and undergo epigenetic modifications that give rise to a very special and stable phenotype.”
These NK cells, called ‘g-NK’ cells, have several characteristics that make them excellent candidates for developing into cell therapies. First, they can be produced as off-the-shelf therapies, in contrast to the approved chimeric antigen receptor (CAR)-T cell therapies for blood cancers, which require a time-consuming and expensive manufacturing process using cells derived from each individual patient. Second, differences in the receptor repertoire of g-NK cells compared with conventional NK cells make them highly suitable for combination with monoclonal antibody therapeutics that target proteins expressed on pathogenic cells.
Their key difference is the absence of expression of FcεRIγ, an adaptor protein that regulates 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 the target cells. The lack of FcεRIγ on g-NK cells alters CD16’s activity, resulting in the release of more cancer-killing factors following interaction with an antibody-coated target cell and thus dramatically enhancing ADCC.
To exploit this feature, Indapta aims to combine g-NK cells with monoclonal antibodies. Many therapeutic antibodies target cancer cells via ADCC, relying on endogenous NK cells to elicit this response. However, NK cell function is often compromised in cancer patients. Combination therapy with g-NK cells might overcome this issue. “The idea is that if you combine an [FDA approved] monoclonal antibody with adoptive NK cell therapy, you provide the NK cells that can mediate the ADCC,” Mandl says.
Indapta raised $60 million of series A financing and is now testing their first g-NK cell product, called IDP-023. In this phase I/II clinical trial involving patients with advanced blood cancers, IDP-23 will be tested first to establish its safety with or without interleukin-2, an approved cancer immunotherapy. Depending on the type of blood cancer that the patient has, it will then be combined either with daratumumab, a therapeutic antibody targeting CD38 on myeloma cells that is approved for treating multiple myeloma, or rituximab, which targets CD20 on B cells and is approved for treating non-Hodgkin lymphoma. The US Food and Drug Administration recently granted IDP-23 fast track designation, a process designed to get drugs to patients quicker. “That’s really recognizing the potential of this therapy to address a significant unmet medical need,” says Mandl. Early observations from a single multiple myeloma patient in the trial treated only with the g-NK cells have been encouraging. “This patient has shown very good partial response, and we’re very excited about that.”
g-NK cells could find many applications in anticancer treatment and beyond. “I think this is where the [NK cell therapy] field is moving towards,” says Karl-Johan Malmberg, an immunologist who works on a competing platform at the University of Oslo and Karolinska Institute. g-NK cells can be easily combined with different monoclonal antibodies, antibody–drug conjugates or other innate immune system engagers to alter target specificity. “This allows us to quickly expand into different clinical indications,” Mandl continues. For cancer, Indapta hopes to move into solid tumors one day.
However, Indapta will initially focus on expanding their pipeline to target autoimmune disease. This decision is driven by the fact that g-NK cells are negative for the inhibitory receptor NKG2A while expressing high levels of the activating NKG2C receptor. 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 powerful NKG2A–HLA-E interaction inhibits undesirable targeting of healthy tissue. However, many diseased cells upregulate HLA-E expression to evade immune surveillance. g-NK cells can counteract this adaptation by favoring the activating NKG2C–HLA-E interaction. A recent study4 published in Cell showed that a subset of NK cells with high NKG2C expression can kill autoreactive B and T cells. The potency of this NK cell response was associated with a reduced risk of developing multiple sclerosis (MS) in healthy individuals, and it was generally weak in patients with MS. “The phenotype and origin of those cells are highly overlapping with our cell product,” says Mandl. She thinks that Indapta’s cells might be an ideal therapy for patients with MS. g-NK cells could eliminate autoreactive B cells in combination with a therapeutic antibody while also getting rid of the HLA-E-expressing autoreactive T cells through direct NKG2C–HLA-E targeting, addressing an important aspect of MS that “CAR T cell therapy will not take care of.” Unlike the specific receptor repertoire of g-NK cells that allow them to perform this dual action, CAR T cells are engineered to express a single receptor that recognizes an antigen present on a target cell.
Malmberg thinks “it’s a clever idea to harness both ADCC capacity and the ability to target HLA-E positive cells” to treat autoimmune disease. He expects durability — an issue raised with NK cell approaches for cancer — to be less problematic in an autoimmune context. Moreover, Indapta claims that g-NK cells can effectively recognize virally infected cells, which might help to “eliminate the latent viral reservoir [of Epstein-Barr virus] that can lead to flares in autoimmune disease,” according to Mandl. Indapta is preparing to file two Investigational New Drug applications to explore the potential of g-NK cell therapy in MS and autoimmune kidney disease.
g-NK cells do not require engineering to insert genes that enhance their performance, providing potential benefits such as lower costs, easier regulatory approval, and lack of risk of malignancies that arise from vector integration. However, adding a CAR that targets a specific antigen might still be useful in some contexts, according to Malmberg. “If you have an HLA-E-negative target, for example, these cells would function very well based on the CAR.”
Besides enhanced ADCC and targeting of HLA-E positive cells, Malmberg is excited about another feature that makes g-NK cells potent killers. Work on his platform has shown that g-NK cells — or ADAPT-NK cells, as he calls them — 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 self-HLA class I ligands to dampen NK cell responses towards normal tissues. The fact that g-NK cells express only one KIR can be exploited to overcome this inhibitory effect on the part of tumor cells. A 2022 study5 from his laboratory showed that mismatching single KIR+ ADAPT-NK cells with tumor cells lacking the corresponding KIR ligand led to increased alloreactivity against leukemia.
A key hurdle to developing these cells into therapeutic products is manufacturing. Compared with NK cells, g-NK cells are harder to expand as a result of their lower proliferative capacity. Indapta has not disclosed its manufacturing process, but according to Mandl, it “has spent a lot of time and effort to optimize the manufacturing process and overcome scale-up hurdles.” If successfully brought to market, g-NK cells’ broad therapeutic utility might fulfill the promise of off-the-shelf NK cell therapy, providing safe and effective treatment to a wide range of patients.
