On April 9, 2024 Mural Oncology plc (Nasdaq: MURA), a clinical-stage immuno-oncology company developing novel, investigational engineered cytokine therapies designed to address areas of unmet need for patients with a variety of cancers, reported poster presentations with pre-clinical data from its Interleukin-18 (IL-18) and IL-12 programs at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) annual meeting taking place April 5-10 in San Diego, California (Press release, Mural Oncology, APR 9, 2024, View Source [SID1234641937]). This is the first time Mural has shared findings from either program. The details for the presentations are as follows, and both posters are available at View Source

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Interleukin-18 engineered for resistance to IL-18 binding protein (IL-18BP) and half-life extension to enhance its therapeutic potential (Abstract #4076):

IL-18 is a potent immune-stimulating cytokine, but it is limited by IL-18 binding protein (IL-18BP) – a secreted high affinity decoy receptor that binds with, and neutralizes, IL-18, thus limiting its efficacy over time.
Mural’s protein engineering approach is twofold: first, it introduces mutations to IL-18 that are designed to minimally impact the structure while eliminating binding to IL-18BP. Secondly, it fuses IL-18 to protein scaffolds to extend the half-life and increase the cytokine’s exposure.
The company believes the half-life enhancement may lead to a more durable immunological effect, as demonstrated by the interferon gamma and Th1 response, proinflammatory reactions necessary for the body’s immune response.
Notably, the duration of Th1 response observed was significantly longer (approximately 7-9 days) than a "naked" approach without this half-life extension, which is generally cleared in 2-3 days.
The optimal balance of potency and pharmacokinetic enhancement is still being determined to nominate a lead IL-18 development candidate.
"Resistance to IL-18BP is the foundation of our approach. The mutations we introduced prevented the binding protein from neutralizing the cytokine’s efficacy. We show that resistance to IL-18BP combined with the drug’s extended half-life leads to a durable immunological effect in preclinical models. Our observation of increases in Th1 cytokines, which have been shown elsewhere to correlate with response to checkpoint inhibitors, are encouraging indications that our engineered IL-18 may provide a therapeutic complement to checkpoint inhibitor immunotherapy1,2," said Mark Whitmore, Ph.D., Principal Scientist of Cancer Biology, and the poster’s lead author.

Generation of tumor targeted self-assembling split IL-12 subunits for the treatment of cancer (Abstract #4066):

IL-12p70 is a potent stimulator of the immune system with profound anti-tumor activity but very poor tolerability.
Mural’s protein engineering approach aims to mitigate IL-12’s hallmark toxicity by splitting the heterodimer into two inactive monomers: IL-12p35 and IL-12p40. These individual subunits are separately fused to two non-competitive antibody fragments.
The goal of this is to assemble active IL-12p70 preferentially in the tumor microenvironment. The sequential administration of these targeted subunits concentrates the IL-12p70 activity primarily at the tumor site, thereby limiting systemic formation and associated toxicities.
In vivo analysis demonstrated that targeting both subunits resulted in the greatest accumulation and retention of IL-12p70 complex in the tumor.
"We believe that by self-assembling the split IL-12 subunits within the tumor microenvironments, we can circumvent native IL-12’s severe toxicities without compromising its efficacy. The data presented today provide strong rationale for our strategy of non-competitively targeting each subunit to a unique epitope on the same molecule," said Joshua Heiber, Ph.D., Director of Research & Development, Cancer Biology, and the poster’s lead author.