FuseBio Presents New Data at AACR: Targeting a Functionally-Selective IL-18 (F-18) to PD-1: A Next Generation Checkpoint Inhibitor with Enhanced Anti-Tumor Activity
FuseBio's unique attenuation mechanism renders IL-18, a functionally selective IL-18, resistant to IL-18BP and 1 million percent less active in circulation and yet still retain nearly full activity when targeted to PD-1+/IL-18R+ cells, the key functional immune cells in tumors. It is designed to retain full activity of PD-1 checkpoint blockade and simultaneously deliver a functionally selective IL-18 (F-18) to preserve and enhance the anti-tumor activity of immune cells.
Woburn, MA, April 09, 2024 --(PR.com)-- Fuse Biotherapeutics, Inc., a biotechnology company developing functionally-selective cytokines for cancer and autoimmune disease, today announced the presentation of new data with respect to their lead asset PD1-F18, at the American Association for Cancer Research (AACR) Annual Meeting being held on April 5-10, 2024, in San Diego, CA. The Fuse Biotherapeutics team will present data on April 9, 2024 that strongly supports the use of PD1-F18 as a highly differentiated PD-1 targeted IL-18 with first and best in class potent single agent antitumor activity.
FuseBio has leveraged its immuno-oncology and protein engineering capabilities to functionally optimize IL-18 (F-18), creating an IL-18 binding protein-resistant molecule with 1 million percent reduced activity in circulation while retaining nearly full affinity for the IL-18 receptor complex when targeted to an immune cell of interest. F-18 was fused onto a PD-1 inhibitor to create a first-in-class PD1-F18 immunocytokine designed for full PD-1 checkpoint blockade while safely delivering IL-18.
“A tremendous amount of effort was made to design a therapeutic to overcome resistance to PD-1 inhibitors such as Keytruda,” said Brian Rabinovich, Ph.D, Chief Scientific Officer of Fuse Biotherapeutics. “Since the immune cells that remain functional and kill tumors in response to PD-1 inhibitors preferentially express the receptor complex for IL-18, the safe and selective delivery of F18 to these cells not only augments their anti-tumor capabilities but also preserves their capacity to respond to a the drug class that placed immunotherapy firmly on the cancer treatment map.” Jeff Takimoto, Ph.D, the Chief Executive Officer of Fuse Biotherapeutics continued, “That we are able to abolish aggressive and PD-1 inhibitor resistant tumors in animal models without side effects is an incredible achievement for our team. We are excited to embark on moving PD1-F18 to the clinic and view our finding as providing much needed hope for the more than 80% of cancer patients that are either resistant or become resistant to PD-1 inhibitors.”
Details regarding the upcoming AACR abstract presentation:
April 9, 2024, 9:00 AM – 12:30 PM (PST)
Poster 4075: Targeting attenuated IL-18 to PD-1: A next generation checkpoint inhibitor with enhanced anti-tumor activity
Abstract Highlights: PD-1 antagonists have shown strong clinical proof of concept, but the development of next-generation versions that can target tumors that weakly respond and/or acquire drug resistance is a critical medical need. Lymphocytes, including T cells and NK cells, upregulate PD-1 and other immunoregulatory receptors in response to neoantigens. Such immunoregulation is important for maintaining the persistence of immune responses in a controllable manner so that immune pathology does not overwhelm the host. In addition to microbial proteins, neoantigens are often expressed by tumor cells. These "tumor antigens" are derived from mutated genes or proteins not presented during T cell education. As such, many established tumors contain areas of chronic inflammation, including a subset of PD-1+ T cells that can be "de-immuno-regulated" by anti-PD-1 antagonist antibodies, thus enhancing anti-tumor activity. IL-18 is a cytokine that delivers a "danger" signal to NK cells and T cell subsets that express the IL-18 receptor complex (RC) and increases their capacity to kill, induces proliferation, diminishes terminal exhaustion, and sustains survival. Importantly, IL-18RC is expressed on progenitor exhausted T cells, the population of T cells in solid tumors that is most active and responds to anti-PD-1, but not terminal exhausted T cells. The latter have been shown to be non-responsive to PD-1 antagonism. Thus, they engineered an anti-PD-1-IL-18 antibody to enhance anti-tumor immune responses. Such a therapeutic requires two key characteristics: resistance to inhibition by IL-18BP, IL-18's natural antagonist, and PD-1-dependent cis-restricted binding to the IL18RC on PD-1+ cells to reduce trans-based systemic toxicity. They have engineered an IL-18BP-resistant mutant of IL-18 and generated variants with different degrees of attenuation for PD-1-dependent cis targeting. Attenuation was achieved by sterically hindering the capacity of IL-18 to bind the IL-18RC while maintaining cis activity without a requirement for proteolytic activation. They identified a variant of IL-18 that is 10,000-fold attenuated and, when fused to an anti-PD-1 antibody, mediated (1) PD-1-dependent cis activity in vitro equivalent to ~5x that of anti-PD-1 alone and (2) tumor shrinkage in mouse tumor models, including an ~80% frequency of complete responses. Due to the high degree of IL-18 attenuation, they were able to dose mice without toxicity to levels at which full PD-1 antagonism is maintained. To their knowledge, this anti-PD-1-IL-18 variant is the first PD-1 targeted cytokine capable of activating PD-1+ T cells via the cytokine’s receptor and fully antagonizing PD-1 as a single agent. Thus, targeting a highly attenuated variant of IL-18 that retains strong cis activity to PD-1 holds promise as a clinical candidate for the treatment of cancer indications that respond weakly to anti-PD-1 and/or are associated with acquired resistance.
The abstract will be made available for viewing on FuseBio’s website upon presentation at the AACR 2024 Annual Meeting (www.fusebiotx.com).
About Fuse Biotherapeutics, Inc.
Fuse Biotherapeutics is a biotechnology company advancing a portfolio of functionally-selective cytokines for cancer and autoimmune disease. Our therapeutics are focused on IL-18, a powerful hormone-like protein that is released in response to danger such as cancer to stimulate the immune system, promotes the survival of immune cells, and oppose late stage immune exhaustion. FuseBio is based in Woburn, MA and is funded by a syndicate of healthcare investors.
Contact: bd@fusebiotx.com
FuseBio has leveraged its immuno-oncology and protein engineering capabilities to functionally optimize IL-18 (F-18), creating an IL-18 binding protein-resistant molecule with 1 million percent reduced activity in circulation while retaining nearly full affinity for the IL-18 receptor complex when targeted to an immune cell of interest. F-18 was fused onto a PD-1 inhibitor to create a first-in-class PD1-F18 immunocytokine designed for full PD-1 checkpoint blockade while safely delivering IL-18.
“A tremendous amount of effort was made to design a therapeutic to overcome resistance to PD-1 inhibitors such as Keytruda,” said Brian Rabinovich, Ph.D, Chief Scientific Officer of Fuse Biotherapeutics. “Since the immune cells that remain functional and kill tumors in response to PD-1 inhibitors preferentially express the receptor complex for IL-18, the safe and selective delivery of F18 to these cells not only augments their anti-tumor capabilities but also preserves their capacity to respond to a the drug class that placed immunotherapy firmly on the cancer treatment map.” Jeff Takimoto, Ph.D, the Chief Executive Officer of Fuse Biotherapeutics continued, “That we are able to abolish aggressive and PD-1 inhibitor resistant tumors in animal models without side effects is an incredible achievement for our team. We are excited to embark on moving PD1-F18 to the clinic and view our finding as providing much needed hope for the more than 80% of cancer patients that are either resistant or become resistant to PD-1 inhibitors.”
Details regarding the upcoming AACR abstract presentation:
April 9, 2024, 9:00 AM – 12:30 PM (PST)
Poster 4075: Targeting attenuated IL-18 to PD-1: A next generation checkpoint inhibitor with enhanced anti-tumor activity
Abstract Highlights: PD-1 antagonists have shown strong clinical proof of concept, but the development of next-generation versions that can target tumors that weakly respond and/or acquire drug resistance is a critical medical need. Lymphocytes, including T cells and NK cells, upregulate PD-1 and other immunoregulatory receptors in response to neoantigens. Such immunoregulation is important for maintaining the persistence of immune responses in a controllable manner so that immune pathology does not overwhelm the host. In addition to microbial proteins, neoantigens are often expressed by tumor cells. These "tumor antigens" are derived from mutated genes or proteins not presented during T cell education. As such, many established tumors contain areas of chronic inflammation, including a subset of PD-1+ T cells that can be "de-immuno-regulated" by anti-PD-1 antagonist antibodies, thus enhancing anti-tumor activity. IL-18 is a cytokine that delivers a "danger" signal to NK cells and T cell subsets that express the IL-18 receptor complex (RC) and increases their capacity to kill, induces proliferation, diminishes terminal exhaustion, and sustains survival. Importantly, IL-18RC is expressed on progenitor exhausted T cells, the population of T cells in solid tumors that is most active and responds to anti-PD-1, but not terminal exhausted T cells. The latter have been shown to be non-responsive to PD-1 antagonism. Thus, they engineered an anti-PD-1-IL-18 antibody to enhance anti-tumor immune responses. Such a therapeutic requires two key characteristics: resistance to inhibition by IL-18BP, IL-18's natural antagonist, and PD-1-dependent cis-restricted binding to the IL18RC on PD-1+ cells to reduce trans-based systemic toxicity. They have engineered an IL-18BP-resistant mutant of IL-18 and generated variants with different degrees of attenuation for PD-1-dependent cis targeting. Attenuation was achieved by sterically hindering the capacity of IL-18 to bind the IL-18RC while maintaining cis activity without a requirement for proteolytic activation. They identified a variant of IL-18 that is 10,000-fold attenuated and, when fused to an anti-PD-1 antibody, mediated (1) PD-1-dependent cis activity in vitro equivalent to ~5x that of anti-PD-1 alone and (2) tumor shrinkage in mouse tumor models, including an ~80% frequency of complete responses. Due to the high degree of IL-18 attenuation, they were able to dose mice without toxicity to levels at which full PD-1 antagonism is maintained. To their knowledge, this anti-PD-1-IL-18 variant is the first PD-1 targeted cytokine capable of activating PD-1+ T cells via the cytokine’s receptor and fully antagonizing PD-1 as a single agent. Thus, targeting a highly attenuated variant of IL-18 that retains strong cis activity to PD-1 holds promise as a clinical candidate for the treatment of cancer indications that respond weakly to anti-PD-1 and/or are associated with acquired resistance.
The abstract will be made available for viewing on FuseBio’s website upon presentation at the AACR 2024 Annual Meeting (www.fusebiotx.com).
About Fuse Biotherapeutics, Inc.
Fuse Biotherapeutics is a biotechnology company advancing a portfolio of functionally-selective cytokines for cancer and autoimmune disease. Our therapeutics are focused on IL-18, a powerful hormone-like protein that is released in response to danger such as cancer to stimulate the immune system, promotes the survival of immune cells, and oppose late stage immune exhaustion. FuseBio is based in Woburn, MA and is funded by a syndicate of healthcare investors.
Contact: bd@fusebiotx.com
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