AIMGlucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as potent drug development target for treating diabetes and obesity. Here, we designed and evaluated novel long-acting GLP-1R G protein biased agonist with potent clinical application.MAIN METHODSGLP-1R G-protein biased sequences were screened via a high-throughput autocrine-based strategy and then fused to Exendin (9-39). These fusion peptides were further performed with site-specific modification. Surface plasmon resonance (SPR) measurements, GLP-1R activation potencies and plasma stability tests were applied to screen optimal candidate. Acute and chronic hypoglycemic and insulinotropic activities of selected agent were evaluated in diabetic and obese rodent animals.MAIN FINDINGSAX09 exert highest binding affinities for GLP-1R extracellular domain (GLP-1R ECD). Further in vitro plasma stability and GLP-1R activation assays demonstrated better potency of AX18. Acute pharmacodynamic evaluation of AX18 demonstrated the promising insulinotropic and hypoglycemic activities which were exhibited in a dose-dependent manner. Prolonged hypoglycemic efficacies of AX18 were also observed in both hypoglycemic duration test and multiple oral glucose tolerance tests (OGTTs) in the diabetic mice. Further pharmacokinetic test in cynomolgus monkeys exhibited that the half-life of AX18 was more than 6 days. Once weekly treatment of AX18 in diabetic mice for 8-week achieved significantly improved %HbA1C, insulin resistance, glucose tolerance, β-cells and diabetic retinal injury. Chronic treatment of AX18 in diet-induced obese (DIO) mice also exhibited beneficial efficacies on %HbA1C, inflammation-related factors lowering, and weight gains.CONCLUSIONAX18, as a novel GLP-1R G protein biased agonist, exhibited potency for treating diabetes mellitus and its complications.

CancersQ2 · MEDICINE

Development of a VLP-Based Vaccine Displaying an xCT Extracellular Domain for the Treatment of Metastatic Breast Cancer

Q2 · MEDICINE

ArticleOA

Author: Lamolinara, Alessia ; Conti, Laura ; Rolih, Valeria ; Pericle, Federica ; Bolli, Elisabetta ; Caldeira, Jerri ; Barutello, Giuseppina ; Parra, Karla ; Iezzi, Manuela ; Cavallo, Federica ; Magri, Jolanda ; Riccardo, Federica ; Valenzuela, Paloma ; Salameh, Ahmad ; Francia, Giulio

Metastatic breast cancer (MBC) is the leading cause of cancer death in women due to recurrence and resistance to conventional therapies. Thus, MBC represents an important unmet clinical need for new treatments. In this paper we generated a virus-like particle (VLP)-based vaccine (AX09) to inhibit de novo metastasis formation and ultimately prolong the survival of patients with MBC. To this aim, we engineered the bacteriophage MS2 VLP to display an extracellular loop of xCT, a promising therapeutic target involved in tumor progression and metastasis formation. Elevated levels of this protein are observed in a high percentage of invasive mammary ductal tumors including triple negative breast cancer (TNBC) and correlate with poor overall survival. Moreover, xCT expression is restricted to only a few normal cell types. Here, we tested AX09 in several MBC mouse models and showed that it was well-tolerated and elicited a strong antibody response against xCT. This antibody-based response resulted in the inhibition of xCT’s function in vitro and reduced metastasis formation in vivo. Thus, AX09 represents a promising novel approach for MBC, and it is currently advancing to clinical development.

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Indication	Highest Phase	Country/Location	Organization	Date
Metastatic breast cancer	Preclinical	US	Agilvax, Inc.	08 Jun 2020
Metastatic breast cancer	Preclinical	IT	University of Turin	08 Jun 2020
Triple Negative Breast Cancer	Preclinical	US	Agilvax, Inc.	01 Jul 2017
Non-Small Cell Lung Cancer	Preclinical	US	Agilvax, Inc.	-

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