1300 Modulation of IL-12p70 exposure and activity following sequential administration of tumor targeted self-assembling split IL-12 subunits

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Background The introduction of immune checkpoint inhibitors was a significant breakthrough in cancer treatment offering substantial benefits for many patients. Nonetheless, many patients fail to respond, develop resistance, or face intolerable side effects, underscoring the need for further advancements in immunotherapy. Cytokines, a group of immunomodulatory proteins, are among the promising candidates to augment and enhance immunotherapies, but their effectiveness has been limited by rapid elimination from the body or pleiotropic nature. Exogenously administered IL-12 exhibits potent immune-stimulating properties and significant anti-tumor effects; however, its clinical utility has been limited by poor systemic tolerance at potentially efficacious dose levels. Thus, development of a systemic immunotherapy that releases the therapeutic potential of IL-12 could offer substantial clinical benefits. Methods Mural Oncology has developed an innovative approach to mitigate the toxicity of IL-12 by splitting the heterodimer into inactive p35 and p40 monomers. The individual subunits are separately fused to two non-competitive antibody fragments targeting a highly expressed tumor-associated antigen. The goal of this approach is to assemble active IL-12 preferentially in the tumor microenvironment (TME). This is achieved by sequential administration of the tumor-targeted subunits, which results in reduced systemic IL-12 exposure while maintaining its exposure in tumor. Pharmacokinetic (PK) and pharmacodynamic (PD) profiles were assessed using plate based analytical methods in preclinical mouse models, including wild type BALB/c mice, tumor bearing immunocompromised mice, and tumor and non-tumor bearing humanized mice. Results These studies demonstrated that by increasing the interval of time between subunit injections, IL-12p70 levels in the peripheral blood were significantly reduced compared to the TME. This data supported modeling efforts and dose selection for studies in which targeted IL-12p35 and targeted IL-12p40 subunits were tested in non-tumor bearing non-human primates. PK and PD peripheral blood biomarkers (soluble, and cellular measured by flow cytometry) demonstrated that the serum exposure and subsequent response to IL-12p70 complex can be successfully reduced by increasing the interval between subunit administrations, or by reducing the dose level of the second subunit administered. Conclusions Results thus far show that the innovative approach of tumor targeted self-assembling split IL-12 could enhance the overall therapeutic potential of this cytokine.