Sonnet BioTherapeutics Announces the Generation and Characterization of Two Novel Immunotherapeutic Pipeline Drug Candidates, SON-1411 and SON-1400, Each Containing a Variant IL-18 Domain

Rhea-AI Summary

Sonnet BioTherapeutics (NASDAQ:SONN) announced the development of two new immunotherapeutic drug candidates, SON-1411 and SON-1400, utilizing a modified IL-18 variant. SON-1411 combines IL-18BPR with IL-12 via Sonnet’s FHAB platform, while SON-1400 solely integrates IL-18BPR with FHAB. These candidates exhibit high bioactivity and target tumor environments more effectively, mitigating the inhibitory effects of IL-18BP. SON-1411 and SON-1400 were produced in CHO cells and E. coli, respectively, and show promising in vitro results for cancer treatment by enhancing immune response against tumors. The new IL-18 variant maintains receptor binding while avoiding IL-18BP inhibition, showcasing potential for broad oncological and cell-based therapies.

Positive

• Development of two new drug candidates, SON-1411 and SON-1400, broadening Sonnet's pipeline.
• SON-1411 and SON-1400 exhibit high bioactivity in receptor binding assays.
• SON-1411 combines IL-18BPR and IL-12 for enhanced therapeutic potential.
• Utilization of Sonnet's proprietary FHAB platform to improve targeting and half-life of drugs.
• Production in CHO cells and E. coli achieved high purity and yield.
• Potential for expanded cancer immunotherapy applications with reduced IL-18BP inhibition.
• Clinical application of these candidates may enhance oncology treatment options.

Negative

• Current data is to in vitro results; no clinical trial data presented.
• Historically, IL-18 has shown poor efficacy in clinical trials due to IL-18BP inhibition.
• Potential financial risk if upcoming clinical trials do not show significant improvement over previous IL-18 therapies.
• Uncertainty about the timeline for clinical trials and market approval.

Insights

Oncology Doctor

Sonnet BioTherapeutics' development of novel immunotherapeutic drug candidates SON-1411 and SON-1400, particularly with their modifications to Interleukin-18 (IL-18), stands out in the oncology landscape. IL-18 plays a important role in modulating immune responses, a vital aspect in cancer treatment. Past trials with IL-18 faced efficacy challenges due to its interactions with IL-18 Binding Protein (IL-18BP), which limited its therapeutic potential. Sonnet's innovative approach to create an IL-18 variant that bypasses this inhibitory pathway can be transformative. This breakthrough could reinvigorate the interest in IL-18-based therapies, potentially leading to more effective cancer immunotherapies. Additionally, the combination of IL-18 and IL-12 in SON-1411 might offer a synergistic effect, further enhancing anti-tumor activity. This development could broaden the scope of immunotherapy applications, providing oncologists with more tools to combat various types of cancer.

Medical Research Analyst

The characterization of SON-1411 and SON-1400 represents a significant stride in the development of targeted immunotherapeutic solutions. The proprietary modifications to IL-18, reducing its binding to IL-18BP while retaining its receptor activity, address a critical limitation in previous IL-18 therapies. This innovation, coupled with Sonnet's FHAB platform, promises extended half-life and enhanced tumor targeting, which are important for effective cancer treatment. By enabling sustained bioactivity and refined delivery to tumor sites, these advancements likely will improve the therapeutic window and efficacy of the treatments, essential factors for clinical success. Investors should note that these developments not only demonstrate scientific ingenuity but also underline Sonnet's potential to position itself strategically within the competitive oncology market. The successful translation of these preclinical results into clinical outcomes could significantly impact the company’s valuation and market standing.

Market Research Analyst

From a market perspective, Sonnet BioTherapeutics' announcement is promising as it signifies progress in its drug pipeline, which is a critical factor for investor confidence. The potential commercialization of SON-1411 and SON-1400 hinges on successful clinical trials, but the preliminary in vitro results are encouraging. The biotech sector highly values innovation and proprietary technology, which Sonnet is leveraging with its FHAB platform. By potentially addressing a known limitation in IL-18-based cancer therapies, Sonnet may carve out a competitive advantage. However, investors should be cautious of the typical risks associated with clinical-stage biotech firms, such as regulatory hurdles and the uncertainty of clinical trial outcomes. Short-term stock volatility is expected, but long-term prospects could be lucrative if these candidates successfully navigate clinical phases and achieve market approval.

• Sonnet discovered and characterized a modified version of Interleukin-18 (IL-18^{Binding Protein Resistant} or IL-18^BPR) that exhibits wild-type binding to the IL-18 receptor (IL-18Rc), coupled with undetectable binding to the inhibitory IL-18 Binding Protein (IL-18BP)
• IL-18^BPR was linked to Sonnet’s proprietary tumor targeting F_HAB platform, with or without single-chain wild-type IL-12
• The bifunctional SON-1411 molecule is manufactured in Chinese Hamster Ovary (CHO) cells, while the monofunctional SON-1400 molecule is made in E. coli; both have been highly purified and were bioactive in the receptor binding assays
• IL-18^BPR and IL-12 could be combined for broad applications in oncology and cell-based therapies

PRINCETON, N.J., June 13, 2024 (GLOBE NEWSWIRE) -- Sonnet BioTherapeutics Holdings, Inc. (NASDAQ:SONN) (the "Company" or "Sonnet"), a clinical-stage company developing targeted immunotherapeutic drugs, announced today the generation and in vitro characterization of two novel drug candidates, SON-1411 (IL18^BPR-F_HAB-IL12) and SON-1400 (IL18^BPR-F_HAB), each containing a modified version of recombinant human interleukin-18 (IL-18^BPR). SON-1411 is a proprietary bifunctional fusion protein consisting of IL-18^BPR combined with single-chain wild-type IL-12, linked to Sonnet's Fully Human Albumin Binding (F_HAB^®) platform, which will replace SON-1410 as a development target. SON-1400 is a monofunctional fusion protein comprising the same IL-18^BPR domain linked to the F_HAB. F_HAB extends the half-life and biological activity of linked molecules by binding native albumin in the serum and targets the tumor microenvironment (TME) through high affinity binding to glycoprotein 60 (gp60) and the Secreted Protein Acidic and Rich in Cysteine (SPARC).

IL-18 can regulate both innate and adaptive immune responses through its effects on natural killer (NK) cells, monocytes, dendritic cells, T cells, and B cells. IL-18 acts synergistically with other pro-inflammatory cytokines to promote interferon-γ (IFN-γ) production by NK cells and T cells. Systemic administration of IL-18 has been shown to have anti-tumor activity in several animal models. Moreover, tumor-infiltrating lymphocytes (TILs) express more IL-18 receptors than other T cells. However, IL-18 clinical trials have shown that, although it is well tolerated, IL-18 has poor efficacy in the treatment of cancers, most likely due in large part to the high co-expression of IL-18 binding protein (IL-18BP) in the TME. In particular, IL-18BP serves as a “decoy receptor” that binds to IL-18 with higher affinity, compared with the IL-18Rc complex, thereby causing a negative feedback loop with IL-18 and inhibiting IL-18-mediated TIL activation. Thus, there exists a potential for the discovery of IL-18 variant compositions that could harness the therapeutic potential of IL-18 for the treatment of cancers.

Sonnet’s strategy for amino acid modifications to rIL-18 was based on a compilation of literature review, 3D X-ray crystallography structures, and computer modeling analysis. Subsequently, certain IL-18 variant sequences were synthesized, engineered into expression constructs and manufactured at small scale in either CHO cell culture or E. coli. Highly purified milligram quantities of SON-1411 or SON-1400 were analyzed in vitro for IL-18Rc or IL-18BP binding activities, respectively, using the HEK-Blue™ and Bright-Glo Luciferase™ IL-18Rc reporter assays. In vitro results for at least one variant of IL-18 showed equivalent binding to the IL-18 Rc, compared to the wild-type IL-18 reference molecule, concomitant with no or reduced binding to IL-18BP.

“The development of a modified IL-18 has been a challenging scientific achievement. IL-18 is a key cytokine that, when combined synergistically with IL-12, has the potential to be an important therapeutic asset for oncology and cell-based therapy. We believe that these novel molecules combined with our proprietary F_HAB platform are expected to demonstrate tumor targeting and longer half-lives, which in turn are expected to allow a therapeutic window for commercialization of these important oncology candidates,” said Pankaj Mohan, Ph.D., Sonnet Founder and Chief Executive Officer.

“The known MOA of IL-18 inhibition by IL-18BP is reviving the importance of clinical applications of IL-18. IL-18BP has been shown to be elevated in cancer patients, thus negating the clinical use of IL-18. Sonnet is excited about the development of a novel bifunctional cytokine molecule, IL18^BPR-F_HAB-IL12, which contains a unique IL18 domain that does not bind the inhibitor IL-18BP but still maintains full IL-18 and IL-12 bioactivity. The clinical application of this bifunctional fusion protein could potentially expand immunotherapy applications for cancer patients,” commented John Cini, Ph.D., Sonnet Chief Scientific Officer.

About SON-1411

SON-1411 is a candidate immunotherapeutic recombinant drug that is closely related to and will replace SON-1410, which links an unmodified single-chain human IL18 and an unmodified IL-12 with the albumin-binding domain of the single-chain antibody fragment A10m3. The only difference between SON-1410 and SON-1411 is that in the latter, the IL-18 domain has been modified via mutagenesis to retain wildtype binding to the IL-18 receptor (IL-18 Rc) while inhibiting or abolishing binding to the IL-18 binding protein (IL-18 BP). The A10m3 scFv was selected to bind both at normal pH, as well as at the acidic pH that is typically found in the TME. The F_HAB technology targets tumor and lymphatic tissue, providing a mechanism for dose sparing and an opportunity to improve the safety and efficacy profile of IL-18 and IL-12, as well as a variety of potent immunomodulators that can be added using the platform. Interleukin-12 can orchestrate a robust immune response to many cancers and pathogens. Given the types of proteins induced in the TME, such as SPARC and gp60, several types of cancer such as non-small cell lung cancer, melanoma, head and neck cancer, sarcoma, and some gynecological cancers are particularly relevant for this approach. SON-1411 is designed to deliver IL-18^BPR and IL-12 to local tumor tissue, turning ‘cold’ tumors ‘hot’ by stimulating IFNγ, which activates innate and adaptive immune cell responses and increases the production of Programed Death Ligand 1 (PD-L1) on tumor cells.

About Sonnet BioTherapeutics Holdings, Inc.

Sonnet BioTherapeutics is an oncology-focused biotechnology company with a proprietary platform for innovating biologic drugs of single or bifunctional action. Known as F_HAB (Fully Human Albumin Binding), the technology utilizes a fully human single chain antibody fragment (scFv) that binds to and "hitch-hikes" on human serum albumin (HSA) for transport to target tissues. Sonnet's F_HAB was designed to specifically target tumor and lymphatic tissue, with an improved therapeutic window for optimizing the safety and efficacy of immune modulating biologic drugs. F_HAB is the foundation of a modular, plug-and-play construct for potentiating a range of large molecule therapeutic classes, including cytokines, peptides, antibodies, and vaccines.

Forward-Looking Statements

This press release contains certain forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934 and Private Securities Litigation Reform Act, as amended, including those relating to the outcome of the Company’s clinical trials, the Company's cash runway, the Company's product development, clinical and regulatory timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statements that are predictive in nature. These forward-looking statements are based on current expectations, estimates, forecasts and projections about the industry and markets in which we operate and management's current beliefs and assumptions.

These statements may be identified by the use of forward-looking expressions, including, but not limited to, "expect," "anticipate," "intend," "plan," "believe," "estimate," "potential, "predict," "project," "should," "would" and similar expressions and the negatives of those terms. These statements relate to future events or our financial performance and involve known and unknown risks, uncertainties, and other factors which may cause actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. Such factors include those set forth in the Company's filings with the Securities and Exchange Commission. Prospective investors are cautioned not to place undue reliance on such forward-looking statements, which speak only as of the date of this press release. The Company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.

Sonnet BioTherapeutics Investor Contact
Jack Yauch
Solebury Strategic Communications
862-754-1024
jyauch@soleburystrat.com

SOURCE: Sonnet BioTherapeutics, Inc.

FAQ

What are the new drug candidates announced by Sonnet BioTherapeutics?

Sonnet BioTherapeutics announced SON-1411 and SON-1400, both containing a modified IL-18 variant.

What makes SON-1411 different from SON-1400?

SON-1411 combines IL-18BPR with IL-12 on Sonnet’s FHAB platform, while SON-1400 only includes IL-18BPR.

How were SON-1411 and SON-1400 produced?

SON-1411 was produced in Chinese Hamster Ovary (CHO) cells, and SON-1400 was produced in E. coli.

What is the significance of the modified IL-18 in SON-1411 and SON-1400?

The modified IL-18 shows wild-type receptor binding with reduced binding to the inhibitory IL-18BP, enhancing tumor targeting and immune response.

How do SON-1411 and SON-1400 improve cancer treatment?

These candidates enhance immune response against tumors and mitigate the inhibitory effects of IL-18BP, showing potential for broader oncological applications.

What is the potential impact of these new drug candidates on Sonnet's stock (SONN)?

The successful development and clinical approval of SON-1411 and SON-1400 could positively impact Sonnet's stock by broadening its therapeutic pipeline and improving cancer treatment options.