Sonnet BioTherapeutics Holdings, Inc. announced that two IND-enabling toxicology studies have been completed in non-human primates (NHPs) using its lead bifunctional therapeutic candidate. SON-1210 is a proprietary, bispecific version of human Interleukins 12 (IL-12) and 15 (IL-15), configured using Sonnet's Fully Human Albumin Binding (FHAB®) platform. The first of two studies, a non-GLP toxicology study, was designed to elucidate the maximum tolerated dose (MTD) of SON-1210 in a dose-escalation format in four cohorts of NHPs.

The second study was a GLP repeat-dose toxicology study that employed three dose levels of SON-1210 or a vehicle control, each dosed three times every two weeks. The GLP study included a six-week recovery period for the high dose and vehicle control groups following the completion of the dosing phase. There were no SON-1210-related increases in toxicity, including liver enzymes, in the GLP study apart from the expected, and mild, on-target changes in hematology and clinical chemistry parameters that resolved completely within 14 to 21 days post-dosing.

A significant increase in interferon gamma (IFNg), which was transient in nature, was noted as early as one day following administration, with no apparent increase in other proinflammatory cytokines. IFNg is a well-known pharmacodynamic biomarker that is required for anti-tumor efficacy in preclinical models. Other signs of cytokine imbalance, or uncontrolled increase of pro-inflammatory cytokines (including TNF-a, IL-1ß, and IL-6) were notably absent from all dose levels tested in the study.

SON-1210 is an immunotherapeutic bispecific, bifunctional drug candidate that links unmodified single-chain human IL-12 and human IL-15 with the albumin-binding domain of the single-chain antibody fragment FHAB separating the two cytokines with linkers to avoid steric hindrance. The FHAB single chain was selected to bind equally well at normal pH, as well as at an acidic pH typically found in the tumor microenvironment (TME). The FHAB technology targets tumor and lymphatic tissue, providing a mechanism for dose-sparing, enhanced pK, and an opportunity to improve the safety and efficacy profile of not only IL-12 and IL-15, but a variety of other potent immunomodulators using the platform.

The company believe Interleukin 12 can orchestrate a robust immune response to many cancers and pathogens. Given the types of proteins induced in the TME, such as Secreted Protein Acidic and Rich in Cysteine (SPARC), 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-1210 is designed to deliver IL-12 and IL-15 to local tumor tissue, with the intention of turning ‘cold' tumors ‘hot' by stimulating IFNg, which activates both innate and adaptive immune cells in the TME, as well as increasing the production of Programed Death Ligand 1 (PD-L1) on tumor cells.