Our Science
Interleukin-18 (IL-18) as a therapeutic
Interleukin-18 (IL-18) is a potent multi-functional cytokine known for its robust immunostimulatory effects. Its profound and vast biological influence extends beyond immune activation; it can preserve special subsets of immune cells that are responsible for killing tumor in response to checkpoint inhibitors and activate powerful anti-cancer mechanisms across various immune cell types. Despite its promise, the clinical utility of IL-18 therapies has been constrained by the inherent limitations of using natural, unmodified IL-18 as a therapeutic agent. We believe that designing and engineering IL-18 variants to specifically target cells involved in anti-cancer activities will overcome these limitations.
1. Inactive cytokine
2. Proximity (cis) activated cytokine
3. Enhance tumor killing
Our Approach
Functionally-selective IL-18 (F-18): a novel approach to cytokine-based therapy
Interleukin-18 (IL-18) is a potent inflammatory cytokine that stimulates and protects crucial anti-tumor immune cells such as cytotoxic T-cells and natural killer (NK) cells. Its dual stimulation of innate and adaptive immune cells involved in tumor cell killing and durable anti-tumor immunity suggests a wide-ranging potential to combat tumors that initially respond to checkpoint inhibitors as well as those that become resistant, making it a promising candidate for immunotherapy.
Major hurdles in the development of IL-18 based therapies:
01
Inhibition of natural IL-18:
IL18 is inhibited by IL-18 Binding Protein (IL-18BP). Cells in the tumor environment produce high levels of an IL-18BP that while effective at preventing chronic and non-targeted proinflammatory responses, blocks IL-18’s effectiveness in cancer
02
Uncontrolled activity of IL-18BP resistant IL-18:
Developing “BP-resistant” IL-18 variants that are completely impervious to IL-18BP, unleashing the full pro-inflammatory effect of IL-18 without any checks-and-balances that can lead to significant side effects in patients
FuseBio is developing a first in class “plug and play” IL-18 that functions selectively by having different affinities toward IL-18BP and IL-18 receptors. Our proprietary method for attenuation results in a Functionally-selective IL-18 that is resistant to IL-18BP, 1 million percent less active in circulation and retains nearly full activity when targeted. This allows FuseBio to unleash the full power of IL-18 onto tumors without any checks-and-balances while minimizing side effects that can occur from a non-targeted, fully active cytokine.
Our lead asset targets F-18 to PD-1 via simple fusion to a clinically verified anti-PD-1 antibody. This drug candidate only delivers a signal through the IL-18 receptor if both PD-1 and the IL-18 receptor are co-expressed on the same cell. In the tumor, these PD-1+ immune cells that also express IL-18 receptor are the tumor killing cells that respond to anti-PD-1 therapies. F-18 is designed to both protect these tumor killing cells from exhaustion and increase their anti-tumor activity.
Complementing F-18 with a highly attenuated interleukin-15 (IL-15)
IL-15 is a cytokine that has been extensively explored as an anti-tumor therapeutic. IL-15 functions in a similar manner to IL-2 to enhance immune cell cytotoxicity and expansion and has been linked to serious side effects and immune exhaustion in the clinic. Our goal is to combine the immune expanding capabilities of IL-15 and the targeted pro-inflammatory properties F-18. To do so, we engineered a variant of IL-15 that is 200,000 percent less active than the natural cytokine (F-15) in circulation but when combined with F-18 and targeted to the appropriate receptor, F-15 can be safely used to expand the targeted immune cell of interest. The capacity to expand specific immune cells in patients in a manner in which F-18 opposes exhaustion may revolutionize immune based therapies that redirect immune cells to tumors, reducing the need or improving more expensive and toxic interventions such as CAR-T.
