Zonhon Biopharma Institute, Inc.

Ovarian stimulation medications are critical in assisted reproductive technology (ART), with growing demand for long-acting follicle-stimulating hormone (FSH). Although luteinizing hormone (LH) plays a pivotal role in oocyte maturation, recombinant long-acting LH remains underexplored. Here we develop a novel recombinant protein with an extended in vivo half-life and dual FSH and LH bioactivity to improve ovarian stimulation efficacy. This protein successfully induced ovarian stimulation in both mice and cynomolgus monkeys, confirming robust reproductive hormonal activity. The findings indicate its potential as an ovarian stimulation agent in ART, although further optimization of stimulation protocols is required.

Mannan (mannose)-binding protein (MBP) is a C-type serum lectin that plays a key role in innate immunity. MBP forms large multimers (200–600 kDa) and exhibits broad specificity for mannose, N-acetylglucosamine, and fucose. MBP exhibits high affinity for unique oligosaccharides that have been isolated from human colorectal carcinoma (SW1116) cells and characterized as highly fucosylated high m.w. type 1 Lewis glycans. In this study, we first demonstrated that MBP recognizes human primary colorectal carcinoma tissues through tumor-associated MBP ligands. We performed fluorescence-based histochemistry of MBP in human colorectal carcinoma tissues and showed that MBP clearly stained cancer mucosae in a Ca2+-dependent manner. Coincubation with plant (Aleuria aurantia) lectin, but not Con A, blocked MBP staining, indicating that fucose, rather than mannose, is involved in this interaction. The expression of MBP ligands was detected in 127 of 330 patients (38.5%), whereas, most significantly, there was no expression in 69 nonmalignant tissues. The MBP-staining pattern in cancer mucosae significantly overlapped with that of Lewis b [Fucα1-2Galβ1-3(Fucα1-4)GlcNAc] staining, but the Lewis b staining in normal tissues was not associated with MBP staining. In addition, the MBP staining correlated inversely with the expression of CA19-9 Ag, and MBP stained 11 of 25 (44%) CA19-9 (sialyl Lewis a [NeuAc(α2-3)Galβ1-3(Fucα1-4)GlcNAc])− colorectal carcinoma tissues. We found a favorable prognosis in patients with MBP ligand+ tumors. These results suggest that selective recognition of cancer cells by endogenous MBP seems to be associated with an antitumor effect and that tissue staining with MBP in combination with CA19-9 may serve as a novel indicator of colorectal carcinoma tissues.

The daily administration of recombinant human growth hormone (rhGH) replacement therapies via subcutaneous (SC) injections can be burdensome for patients. Long-acting Growth hormone (GH) formulation could reduce injection frequency, and it will be expected to increase treatment adherence. ZHB111 is a PEGylated rhGH that requires sc injection every two weeks. This study aims to examine the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of multiple sc doses of ZHB111.

In the PK study, naïve cynomolgus monkeys were divided into four groups with 3/sex/group. Each group received single subcutaneous administration at 0 (control article, Sodium chloride injection), 0.3, 1.0 and 3.0 mg/kg, respectively. To access safety and PD profile, cynomolgus monkeys were randomly assigned to 4 groups of 5/sex/group, and were dosed with ZHB111 once weekly for 4 times by subcutaneous injection at 0 (control article, Sodium chloride injection), 1, 5 or 20.6 mg/kg/dose. Tissue distribution was accessed by administering a single subcutaneous dose of ZHB111 to Sprague-Dawley Rats.

ZHB111 exhibits a significant difference in serum half-life (in monkeys) across varying dosages, with a trend of decreasing half-life as the dosage increases, ranging from 110-30 h. No significant differences were observed between different genders at the same dosage level. After subcutaneous administration of 0.3mg/kg of ZHB111, the mean values of IGF-1 in male animals ranged among 594.93~1294.98ng/mL at various time points, while those in female animals were within the range of 394.15~770.01ng/mL.

The tolerability of ZHB111 was demonstrated in both rat and monkey models, with only minimal adverse effects observed. These findings support the continued clinical development of ZHB111 as a novel treatment for growth hormone deficiency (GHD) in both children and adult patients.