IL12Rβ1 Partial Agonists Are Active with Reduced Toxicity In Vivo

The heterodimeric, T cell–activating cytokine IL12 has been proposed as an anticancer therapy, but toxicity due to off-target activation of natural killer (NK) cells has been problematic. Notably, IL12 shares one of its subunits, p40, with the cytokine IL23, and it is through p40 that IL12 and IL23 bind the receptor IL12Rβ1 on antigen-presenting cells. Using X-ray crystallography and cryo–electron microscopy, Glassman and colleagues determined the structures of various subcomplexes of the IL12–IL12Rβ1 complex and the IL23–IL12Rβ1 complex, elucidating the interfaces between IL12Rβ1 and the shared IL12/IL23 subunit p40. Mechanistically, T cells appeared to upregulate IL12Rβ1 to enhance their sensitivity to IL12, suggesting that an IL12-like IL12Rβ1 partial agonist may be able to activate T cells without activating NK cells. Employing the knowledge gained from the prior experiments enabled informed mutagenesis of the shared interface to develop an IL12-like IL12Rβ1 partial agonist that was capable of activating CD8+ T cells and promoting their production of IFNγ without activating NK cells or promoting their production of cytokines. Importantly, these partial agonists were capable of producing intermediate levels of T cell–mediated antigen-specific killing of tumor cells. In vivo, these IL12Rβ1 partial agonists promoted antitumor T-cell immunity without causing off-target activation of NK cells, leading to reduced toxicity but comparable tumor growth inhibition compared with IL12 in a mouse model of colon adenocarcinoma. Collectively, these results not only reveal the mechanism of IL12Rβ1 activation by IL12 and IL23 but also provide a template for the design of IL12-like IL12Rβ1 partial agonists that may preserve the antitumor effects of IL12 without exhibiting the same toxicity.

Glassman CR, Mathiharan YK, Jude KM, Su L, Panova O, Lupardus PJ, et al. Structural basis for IL-12 and IL-23 receptor sharing reveals a gateway for shaping actions on T versus NK cells. Cell 2021;184:983–99.E24.

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