Sonnet BioTherapeutics Announces U.S. Patent for IL-18 Variant in New Immunotherapeutic Drugs

Sonnet BioTherapeutics Holdings, Inc., a clinical-stage biopharmaceutical company, recently announced the issuance of a new patent by the United States Patent and Trademark Office (USPTO). The patent, numbered 12,134,635, is titled “Interleukin 18 (IL-18) Variants and Fusion Proteins Comprising Same,” and it covers two innovative drug candidates, SON-1411 and SON-1400. These drugs contain modified versions of recombinant human interleukin-18 (IL-18), labeled as IL-18BPR (Binding Protein Resistant).

SON-1411 is a bifunctional fusion protein combining IL-18BPR with single-chain wild-type IL-12, linked to Sonnet’s Fully Human Albumin Binding (FHAB) platform. This new candidate has taken over from SON-1410 as the primary development target. On the other hand, SON-1400 is a monofunctional fusion protein that integrates the IL-18BPR domain with the FHAB. The FHAB platform enhances the half-life and biological activity of these molecules by binding to native albumin in the serum. It targets the tumor microenvironment (TME) through a high affinity for glycoprotein 60 (gp60) and the Secreted Protein Acidic and Rich in Cysteine (SPARC).

IL-18 is known for its role in regulating both innate and adaptive immune responses, affecting natural killer (NK) cells, monocytes, dendritic cells, T cells, and B cells. It works in synergy with other pro-inflammatory cytokines to promote interferon-γ (IFN-γ) production by NK cells and T cells. Studies have shown that systemic administration of IL-18 can have anti-tumor effects in various animal models. Tumor-infiltrating lymphocytes (TILs) express higher levels of IL-18 receptors compared to other T cells. Nevertheless, clinical trials with IL-18 have shown limited efficacy in cancer treatment, largely due to the high levels of IL-18 binding protein (IL-18BP) in the TME, which acts as a decoy receptor, inhibiting IL-18 activity.

Sonnet’s strategy to modify IL-18 involved a detailed process of literature review, 3D X-ray crystallography, and computer modeling analysis. They synthesized and engineered certain IL-18 variant sequences into expression constructs, which were then produced in small-scale cultures of CHO cells or E. coli. The highly purified variants of SON-1411 and SON-1400 were tested in vitro for their binding activities to IL-18Rc and IL-18BP, respectively, using HEK-Blue™ and Bright-Glo Luciferase™ assays. The results showed that at least one IL-18 variant had equivalent binding to the IL-18Rc compared to the wild-type IL-18, along with reduced or no binding to IL-18BP.

Sonnet is also developing bifunctional cytokine molecules, IL-18BPR-FHAB-IL12 and IL-18BPR-FHAB, that contain an IL-18 domain not binding to IL-18BP but maintaining full IL-18 and IL-12 bioactivity. These fusion proteins have the potential to expand immunotherapy options for cancer patients.

SON-1411 is an immunotherapeutic recombinant drug closely related to, and replacing, SON-1410. It links an unmodified single-chain human IL-18 and IL-12 with the albumin-binding domain of A10m3. The main distinction between SON-1410 and SON-1411 lies in the modified IL-18 domain of the latter, which retains wild-type binding to the IL-18 receptor while inhibiting or abolishing binding to IL-18BP. The A10m3 scFv was chosen for its binding capabilities at both normal and acidic pH levels found in the TME. The FHAB technology targets tumors and lymphatic tissue, providing a mechanism for dose sparing and improving the safety and efficacy profiles of IL-18 and IL-12, along with other potent immunomodulators. Interleukin-12 can induce a robust immune response to various cancers and pathogens, making several cancer types, such as non-small cell lung cancer, melanoma, head and neck cancer, sarcoma, and some gynecological cancers, particularly relevant for this approach. SON-1411 aims to deliver IL-18BPR and IL-12 to tumor tissue, converting ‘cold’ tumors to ‘hot’ by stimulating IFNγ, which activates innate and adaptive immune cell responses and increases PD-L1 production on tumor cells.

Sonnet BioTherapeutics Holdings, Inc. focuses on developing targeted biologic drugs for oncology using its proprietary FHAB platform. The technology utilizes a fully human single-chain antibody fragment that binds to human serum albumin for transport to target tissues. Sonnet’s FHAB platform aims to optimize the safety and efficacy of immune-modulating biologic drugs and serves as a modular construct for enhancing various large molecule therapeutic classes.