Be Biopharma, Inc, a company pioneering the discovery and development of Engineered B Cell Medicines (BCMs), presented results from new preclinical research demonstrating production of active ALP by a BCM, which highlights BCMs as a potential treatment for Hypophosphatasia (HPP). Researchers used CRISPR/Cas9 precision gene engineering and artificial intelligence-guided protein design to modify primary human B cells to produce ALP, an enzyme deficient in people living with HPP. The findings were presented during a poster presentation at the American Society of Gene & Cell Therapy (ASGCT) 27th Annual Meeting on Friday, May 10, at 12:00pm ET.
HPP is a rare genetic disease caused by loss of function mutations in the ALPL gene which leads to deficient ALP activity. People living with HPP can experience wide ranging systemic complications, with impaired bone mineralization, such as rickets/osteomalacia, being a major clinical hallmark of severe disease. The only approved therapy for HPP is an enzyme replacement therapy, asfotase alfa, which requires multiple injections every week and is approved only for use in patients with pediatric-onset forms of HPP.
“This study demonstrates how BCMs coupled with artificial intelligence-guided protein design broaden the potential of our medicines to express highly effective conjugated therapeutic proteins such as ALP-Fc fusion proteins,” said Rick Morgan, Chief Scientific Officer. “BCMs are designed to provide constant and durable protein levels without preconditioning, are redosable, and can be applied to a wide range of diseases, including a potential first-in-class medicine for people living with HPP.”
In this study, primary human B cells were expanded and precision engineered by CRISPR/Cas9 genome editing with AAV-mediated homology directed repair (HDR) to insert an ALP gene expression cassette into various loci, including CCR5 (a safe harbor locus). Guided by an artificial intelligence-based ALP protein structure design engine, protein constructs were optimized for activity and stability of ALP-Fc fusion proteins. Engineered BCMs secreted active ALP proteins up to 200 ng/1e6 cells/24hr. Robust in vitro phenotypic correction using ALP secreting BCMs (ALP-BCMs) was demonstrated in the MC3T3 osteoblast precursor mineralization model.
The B cell is a powerful cell that produces thousands of proteins per cell per second at constant levels, and over decades. Precision genome editing can now be used to engineer B Cells that produce therapeutic proteins of interest, driving a new class of cellular medicines – Engineered B Cell Medicines (BCMs) – with the potential to be durable, allogeneic, redosable, and administered without pre-conditioning. The promise of BCMs could transform therapeutic biologics with broad application — across protein classes, patient populations and therapeutic areas.
SOURCE: Businesswire