Be Biopharma Presents Data from Preclinical Studies Showing Engineered B Cells Produce Highly Active Therapeutic Proteins and Demonstrate Durable Engraftment Without Pre-Conditioning

BRUSSELS–(BUSINESS WIRE)–Be Biopharma, Inc. (“Be Bio”), a company pioneering the discovery and development of Engineered B Cell Medicines (BCMs), will present research from preclinical studies during the European Society of Gene & Cell Therapy (ESGCT) 30^th Annual Meeting. In an oral presentation on Friday, October 27, from 11:00 to 13:00 CEST, Be Bio demonstrates that BCMs are capable of producing a variety of therapeutic protein classes using precision gene editing. The data include durable in vivo production of the human clotting factor IX, prevention of tumor growth in a patient-derived xenograft model via a CD19xCD3 bispecific antibody, and engraftment without preconditioning in immunocompetent non-human primates (NHPs). Also being presented are findings from a preclinical study showing BCMs are capable of producing highly active acid sphingomyelinase, the gene defective in Niemann-Pick disease, and correct the disease phenotype in knockout cells.

“The data we are presenting give further evidence that our precision B cell engineering platform enables the expression of diverse therapeutic proteins and represents a promising approach for a new class of medicines with potentially broad therapeutic utility,” said Rick Morgan, Ph.D., chief scientific officer, Be Biopharma. “These data highlight the therapeutic modularity and unique advantages of our BCM platform.”

Today’s gene and cell therapies are potentially transformative medicines which can treat previously intractable diseases. However, there are barriers to the broad adoption of these therapies as current platforms struggle with drawbacks including inability to titrate dose and reliance on toxic preconditioning, among other challenges. Terminally differentiated human plasma cells (PCs) derived from genetically engineered B cells — termed B Cell Medicines, or BCMs — potentially offer natural longevity¹, capacity for high levels of protein secretion (thousands of Ig molecules/cell/sec)², ability to engraft without preconditioning, and the ability to redose.

Study Summary: “Development of an ex vivo precision gene engineered B cell medicine platform and demonstration of engraftment without preconditioning in non-human primates”

BCMs are produced via a CRISPR/Cas9 engineering platform that achieves gene knockouts with greater than 90% efficiency as well as targeted HDR-mediated gene insertions at frequencies as high as 60%. A BCM prototype engineered to express firefly luciferase with a phenotype of >90% CD27+CD38+ was injected via IV into immunodeficient mice, demonstrating rapid bone-marrow-homing and durable engraftment (>100 days). Further illustrating the modularity of the BCM platform, B cells were engineered to produce either lysosomal storage disease (LSD) enzyme acid sphingomyelinase (ASM), clotting factor IX (FIX), or an anti-CD19/CD3 bispecific T cell engager. These examples demonstrated that BCMs can produce proteins with specific activity much higher than standard recombinant proteins (ASM), are stably expressed for over 4 months in vivo (FIX) and show efficacy in tumor treatment (anti-CD19/CD3 scFv). In order to assess engraftment in an immunocompetent model, an ex vivo method was developed to engineer, expand and differentiate non-human primate (NHP) peripheral blood B lymphocytes into PCs. Using zirconium-89-oxine cell radiolabeling and high sensitivity PET/CT tracking, ex vivo expanded and differentiated autologous PCs demonstrated rapid homing and engraftment in PC niches in unconditioned NHPs.

Details for the oral presentation of this study are as follows:

The study was funded and conducted through a collaborative research and development agreement with the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Study Summary: “Development of an ex vivo precision gene engineered B cell medicine that produces highly active and sustained levels of acid sphingomyelinase for the treatment of Niemann-Pick disease”

Niemann-Pick disease (NPD) is an autosomal recessive lysosomal storage disease caused by acid sphingomyelinase (ASM) deficiency. Sphingomyelin accumulates in multiple organs leading to organ failure, and in the severest form causes death early in life. Currently, the only treatment which is approved in NPB, a subset of NPD, is an enzyme replacement therapy (ERT) requiring an intensive dose escalation phase followed by Q2W maintenance intravenous infusions. This study evaluated the potential of engineering B cells to produce therapeutic levels of ASM, thus offering a potential new treatment for NPD.

In this study, primary human B cells were expanded, engineered by CRISPR/Cas9 genome editing with an AAV-delivered template for homology-directed repair (HDR) to insert a constitutive promoter followed by the ASM gene, SMPD1, into a safe harbor locus, which showed up to 30% HDR. BCMs were subsequently expanded and differentiated in vitro. Engineered BCMs secreted ASM up to ~150 ng/1e6 cells/24hr as measured by ELISA. HAP1 SMPD1 knockout cells exposed to supernatant from SMPD1-engineered BCMs restored ASM activity. Liquid chromatography–mass spectrometry analysis demonstrated that HAP1 SMPD1 knockout cells treated with supernatant from SMPD1-engineered BCMs mitigated the accumulation of lyso-sphingomyelin and that BCM-produced ASM was approximately 10-fold more active than recombinant ASM made from CHO cells.

Details for the poster presentation of this study are as follows:

Title: “Development of an ex vivo precision gene engineered B cell medicine that produces highly active and sustained levels of acid sphingomyelinase for the treatment of Niemann-Pick disease”

Lead Author: Monika Musial-Siwek, Ph.D., Director Protein Science, Be Biopharma

Co-Presenters: Timothy Mullen, Ph.D., Senior Scientist, Be Biopharma, Anja Hohmann, Ph.D., Senior Director, Cell Engineering, Be Biopharma

Poster: P579

Poster Session: October 25, 17:00-18:15, and October 26 from 20:30 to 21:30 CEST

About B Cells – A New Class of Cellular Medicines

Imagine what could “Be?” In nature, a single B cell engrafts in the bone marrow and can produce thousands of proteins per second at constant levels over decades. B cells are nature’s exquisite medicine factories, manufacturing proteins to fight disease and maintain health. Unleashing the power of B cells is driving a new class of cellular medicines – Engineered B Cell Medicines (BCMs). BCMs have the potential to be durable, allogeneic, redosable and administered without toxic conditioning. The promise of BCMs could transform therapeutic biologics with broad application — across protein classes, patient populations and therapeutic areas.

About Be Biopharma

Be Biopharma (“Be Bio”) is pioneering Engineered B Cell Medicines (BCMs) to dramatically improve the lives of patients who are living with cancer, rare diseases and other serious conditions. With eyes locked on the patient, our team of purpose-driven scientists, technologists, manufacturing experts and business builders collaborate to create a bold new class of cell therapies. Be Bio was founded in October 2020 by Longwood Fund and B cell engineering pioneers David Rawlings, M.D., and Richard James, Ph.D., from Seattle Children’s Research Institute. Be Bio is backed by ARCH Venture Partners, Atlas Venture, RA Capital Management, Alta Partners, Longwood Fund, Bristol Myers Squibb, Takeda Ventures, Seattle Children’s Research Institute and others. Since our founding, Be Bio’s investors have committed over $180 million to enable the Company to re-imagine medicine based on the power of B cell therapy. For more information, please visit us at Be.Bio and our LinkedIn page.

¹ Landsverk et al (2017) J Exp Med
² Hibi and Dosch (1986) J Immunol; Eyer et al (2017) Nat Biotech