SMPD1

SANTA FE, N.M.--( BUSINESS WIRE )--Be Biopharma, Inc. (“Be Bio”), a company pioneering the development of engineered B Cell Medicines (BCMs), today announced an oral presentation and poster presentation at the Keystone Symposia on Emerging Cellular Therapies meeting, held from January 22 to 25, 2024 in Santa Fe, New Mexico. The data being presented support the utility of engineered B cell medicines (BCMs) across a broad range of applications. Together, the data demonstrate in vitro production and activity of several therapeutic proteins, as well as i n vivo engraftment without preconditioning and activity in multiple model systems. “Gene and cell therapies have transformative potential to treat previously intractable diseases, but have barriers to adoption such as lack of durability, inability to re-dose, and requirement of preconditioning for engraftment. Our BCM platform has the potential to address these barriers,” said Richard A. Morgan, Ph.D., Chief Scientific Officer, Be Bio. “The in vivo preclinical data presented today validates key attributes of our BCM platform – efficient protein production, editing and insertional efficiency, and durable protein production without preconditioning – while demonstrating its potential therapeutic benefits in genetic disease and cancer.” Presentation Summary: Development of an Ex Vivo Precision Gene Engineered B Cell Medicine Platform that Produces Active and Sustained Levels of Therapeutic Proteins with Broad Utility BCMs were produced via a precision genome engineering platform that achieves gene knockouts with greater than 90% efficiency and targeted HDR-mediated gene insertions at up to 60%. Modularity of the BCM platform was demonstrated across multiple models and proteins, including production of firefly luciferase, lysosomal storage disease enzyme acid sphingomyelinase, an anti-CD19/CD3 bispecific T cell engager, clotting factor IX, and fusion protein of tissue nonspecific alkaline phosphatase (ALP). These examples demonstrate that these BCMs can produce proteins with enzyme specific activity higher than recombinant proteins (ASM), show efficacy in tumor treatment (anti-CD19/CD3 scFv), and are stably expressed for at least 20 weeks in vivo (FIX). Engraftment in all models was achieved without preconditioning which broadens BCM clinical utility for patients for whom preconditioning toxicities are unacceptable or outweigh therapeutic benefit, and could facilitate additional rounds of treatment as needed. BCMs capable of expressing therapeutically relevant transgenes have the potential for broad and meaningful therapeutic utility in genetic diseases, cancer, and beyond. Details for the oral presentation of this study are as follows: Title: “Development of an Ex Vivo Precision Gene Engineered B Cell Medicine Platform that Produces Active and Sustained Levels of Therapeutic Proteins with Broad Utility” Lead Author: Hanlan Liu, Ph.D., MBA, Senior VP, Pipeline and Non-clinical Development, Be Biopharma Presenter: Hanlan Liu, Ph.D., MBA, Senior VP, Pipeline and Non-clinical Development, Be Biopharma Date/Time: Tuesday, January 23, 2024, 5:00-7:00pm (MST) Session: Strategies for Engineered Cell Therapies Poster Summary: Development of an Ex Vivo Precision Gene Engineered B Cell Medicine Platform that Produces Active and Sustained Levels of Therapeutic Proteins with Broad Utility in Rare Diseases and Cancer This study demonstrates production of BCMs via editing, expansion and differentiation of primary human B cells. Cells engineered to express firefly luciferase were engrafted into NOG-hIL6 mice and demonstrated in vivo persistence for 125 days. Data are also presented on BCMs engineered to produce FIX, which demonstrates activity via the chromogenic and aPTT assay. These BCMs were engrafted into NOG-hIL6 mice and demonstrate durable FIX secretion to 168 days. In addition to FIX, BCMs were engineered to produce an anti-CD19/CD3 bispecific T cell engager, which demonstrated potent activity in an in vivo PdX model of ALL, ALP, which corrected HPP-related bone mineralization deficits in vitro , and ASM, which demonstrated in vitro phenotypic correction in SMPD1 knockout cells. In addition, ex vivo -rhesus macaque plasma cells were generated and labeled with a radioactive tracer. These cells were administered without preconditioning and demonstrated homing to and engraftment in plasma cell niches in an autologous rhesus macaque. Details for the poster presentation of this study are as follows: Title: “Development of an Ex Vivo Precision Gene Engineered B Cell Medicine Platform that Produces Active and Sustained Levels of Therapeutic Proteins with Broad Utility in Rare Diseases and Cancer” Lead Author: Hanlan Liu, Ph.D., MBA, Senior VP, Pipeline and Non-clinical Development, Be Biopharma Presenter: Hanlan Liu, Ph.D., MBA, Senior VP, Pipeline and Non-clinical Development, Be Biopharma Poster #: 2 Poster Session: Wednesday, January 24, 2024, 7:30pm (MST) About Engineered B Cell Medicines – A New Class of Cellular Medicines The B cell is a powerful cell that produces thousands of proteins per cell per second at constant levels, 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. 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 Hemophilia B and other genetic diseases, cancer, 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 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.

Findings To Be Presented During the European Society of Gene & Cell Therapy 30th Annual Meeting 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) 30th 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: Title: “Development of an ex vivo precision gene engineered B cell medicine platform and demonstration of engraftment without preconditioning in non-human primates” Lead Author: Hanlan Liu, Ph.D., MBA, Senior VP, Pipeline and Non-clinical Development, Be Biopharma Presenter: Rick Morgan, Ph.D., Chief Scientific Officer, Be Biopharma Oral Presentation #: OR-77 Date/Time: Friday, October 27, 11:00-13:00 CEST Session: 11a: Gene editing: Towards clinical trials 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 to 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

Preclinical Research Shows B Cell Medicines Durably Produce Functional Biologics and Engraft without Preconditioning Platform Modularity Drives Creation of B Cell Medicines Across Multiple Diseases CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Be Biopharma, Inc. (“Be Bio”), a company pioneering the discovery and development of Engineered B Cell Medicines (BeCMs), will present preclinical research today showing the precise genome engineering of human B cells to express diverse therapeutic proteins using the company’s proprietary platform. The findings will be presented during an oral session at the American Society of Gene & Cell Therapy (ASGCT) 26th Annual Meeting at 2:15-2:30 p.m. PST with additional data in poster presentation 1453 on Friday, May 19th from 12:00-2:00 p.m. PST. Plasma cells are terminally differentiated B cells, which can live for decades1 and have the capacity to secrete extremely high levels of protein2 making them attractive for the sustained delivery of biologics to treat a wide range of diseases. However, it has historically been challenging to genetically engineer B cells efficiently, precisely, and in a manner that could produce proteins at therapeutic levels over long durations. Leveraging the convergence of advanced gene editing, deep insights into B cell biology and cell therapy technologies, Be Bio has designed a versatile CRISPR/Cas9 engineering platform capable of delivering a gene of interest via homology-directed repair (HDR) to produce stable BeCMs. “In a short two years, Be Bio has validated key concepts of our B cell medicine platform including editing precision and efficiency, reproducible engraftment, and durable functional protein expression with the goal of creating a new class of cellular medicines with broad therapeutic utility,” said Dr. Rick Morgan, Chief Scientific Officer, Be Bio. “B cell medicines have the potential to transform the lives of patients – they can be redosed when required, delivered autologously and allogeneically, and can be administered without preconditioning – offering distinct advantages over other advanced therapies.” Be Bio Platform Attributes Engineering Precision and Efficiency: Depending on the desired therapeutic protein expression level, the platform can target gene insertions to safe harbor sites as well as sites transcriptionally active in B cells. Across transgenes, targeting a transcriptionally active B cell site can enable up to a tenfold increase in protein secretion compared to insertion at the CCR5 safe harbor site. In addition, precisely targeted integration significantly reduces the risk of random gene insertion. Using optimized cell culture and engineering conditions, the platform achieves gene knockouts with greater than 90% efficiency, stable gene insertion via precise HDR with up to 60% efficiency as measured by digital droplet PCR, and multiplexed expression of two genes with efficiencies above 20% as measured by flow cytometry. Durable and Functional Protein Expression: We observed the robustness of the platform through the expression of multiple therapeutic proteins such as Factor IX (FIX) for hemophilia B, acid sphingomyelinase (ASM) for Niemann-Pick Diseases (NPD) and an anti-CD19/CD3 bispecific T cell engager for acute lymphoblastic leukemia (ALL). In each of two donors, FIX was detected in mouse plasma and lasted for greater than 18 weeks post BeCM transfer demonstrating persistence. In a separate experiment, BeCM-secreted ASM corrected the disease phenotype in NPD (SMPD1) gene knock-out cells. In addition, in vitro and in vivo anti-tumor activity was observed. Potent in vitro anti-tumor activity was shown when supernatant from bispecific T cell engager-producing BeCMs directed primary human T cells to kill Raji tumor cells (CD19+). In a study conducted by Be Bio’s scientific co-founders and collaborators from the Seattle Children’s Research Institute, engineered B cells produced bispecific T cell engagers in vivo that mediated T cell activation and showed anti-tumor efficacy in a patient-derived xenograft mouse model3. Rapid Screening: To supplement adeno-associated virus (AAV) vector-mediated HDR, a rapid plasmid-based screening protocol was developed. The plasmid-based platform efficiently identifies the appropriate parameters for the secretion of a given protein of interest in primary B cells enabling rapid development from idea to prototype. The screening protocol assesses gene and protein design parameters for optimal transgene expression levels. Engraftment without Preconditioning: Rapid homing (within one day) and engraftment without preconditioning were shown in two models. In immunodeficient (NOG-hIL6) mice, BeCMs engrafted and persisted for greater than 100 days. In non-human primates with intact immune systems, BeCMs administered by intravenous infusion homed to and engrafted in the bone marrow and spleen. These fundamental platform attributes overcome historical challenges for scalable and effective B cell engineering. The platform has the potential to transform the power of B cells into the development of autologous and allogeneic B cell medicines and unlock a pipeline of product candidates for broad and meaningful therapeutic utility in rare disease, cancer and beyond. # # # 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 (BeCMs). BeCMs have the potential to be durable, allogeneic, redosable and administered without toxic conditioning. The promise of BeCMs 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 (BeCMs) 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 3 Hill et al (2023, May 16-19) Human Plasma Cells Engineered to Produce Bi-Specific T cell Engagers Show In Vivo Anti-Tumor Efficacy [Conference Abstract]. American Society of Gene & Cell Therapy 26 Annual Meeting. View source version on businesswire.com: Contacts Investors and Media: Stephanie Fagan ir@be.bio media@be.bio Source: Be Biopharma, Inc. View this news release online at: