Harnessing NK Cells with IPH6501: A Pioneering Approach to B-Cell Non-Hodgkin Lymphomas

CD20 is a protein found on the surface of mature B-cells and is a common target for treating B-cell non-Hodgkin lymphoma (B-NHL). Despite the availability of several CD20-targeting therapies, there remains a need for innovative approaches for patients who do not respond to standard treatments. Recent studies have shown that natural killer (NK) cells can be effective in treating hematologic malignancies, including B-NHL, with minimal side effects.

Innate Pharma is developing IPH6501, a novel NK cell engager that targets CD20. The therapy is designed to activate NK cells by binding to NKp46 and CD16a receptors, as well as to the interleukin-2 receptor (IL-2R) on NK cells, while also targeting the CD20 antigen on cancerous B cells. The IL-2 component of IPH6501 has been modified to prevent binding to the IL-2Rα chain, reducing the risk of toxicity.

Preliminary results indicate that IPH6501 effectively redirects IL-2 to NK cells, enhancing their activation and proliferation. The therapy has demonstrated potent cytotoxic activity against CD20+ target cells, even those with low CD20 expression levels. In comparison to established CD20-targeting antibodies, IPH6501 has shown superior control of tumor cell growth in vitro.

In vivo studies using a surrogate of IPH6501 have resulted in significant NK cell proliferation and activation in mice. The surrogate also exhibited strong antitumor effects in aggressive B-NHL models, both in immunocompromised and immunocompetent animals. In non-human primates, IPH6501 was well-tolerated and led to NK cell expansion without significant systemic cytokine release.

Analysis of samples from R/R B-NHL patients suggests that NK cell numbers and NKp46 expression are within normal ranges, while CD16 expression is down-regulated in tumor-involved lymph nodes. This indicates a potential advantage of targeting NKp46 with IPH6501. Ex vivo studies with patient samples have shown that IPH6501 can stimulate NK cell proliferation and deplete CD20+ cells, outperforming a control T cell engager.

In summary, IPH6501 is a promising new therapy that leverages the antitumor capabilities of NK cells in CD20+ B-cell malignancies. It is anticipated to enter first-in-human clinical trials in 2023.