On October 31, 2023 Be Biopharma, Inc. ("Be Bio"), a company pioneering the discovery and development of Engineered B Cell Medicines (BCMs), reported that it will present preclinical data demonstrating that a BCM-derived biologic can deliver steady-state plasma concentrations of a bispecific T cell engager at clinically relevant doses for treatment of relapsed/refractory acute lymphoblastic leukemia (ALL) (Press release, Be Biopharma, OCT 31, 2023, View Source [SID1234636517]). Findings from the study, conducted jointly with researchers at Seattle Children’s Research Institute, will be presented during the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 38th Annual Meeting.

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"These findings underscore the clinical potential of BCMs as an emerging platform for sustained delivery of antitumor biologics. Our platform enables production of a diverse set of therapeutic proteins, including those difficult to manufacture using traditional systems, and offers a promising approach for a new class of medicines with broad therapeutic utility," said Dr. Rick Morgan, Chief Scientific Officer, Be Bio.

"Bispecific T cell engagers are highly effective in treating relapsed/refractory ALL; however, their short half-life requires continuous intravenous administration at high doses for four-week increments. This study demonstrates that engineered plasma cells can deliver a constant infusion of bispecific T cell engagers at a steady-state, clinically relevant plasma concentration, offering a potential therapeutic advance to decrease the burden of therapy for patients," said Dr. Richard James, principal investigator at Seattle Children’s Research Institute.

The poster presentation details are as follows:

Saturday, November 4, 2023, 12:10 pm PDT

Session: Session 205a: Rapid Oral Abstract-Basic Science

Title: "Development of ex vivo precision gene engineered B cell medicines that produce highly active and sustained levels of transgenic anti-tumor biologics"

Lead Authors: Rick Morgan, Ph.D., and Richard G. James, Ph.D.

Presenter: Sean Arlauckas, Ph.D., Director, Oncology Research, Be Bio

Abstract #: 409

Bispecific T cell engagers, consisting of an anti-CD3 single-chain fragment variable (scFv) fused to an anti-tumor antigen scFv, are highly effective in the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). However, the short half-life of bispecific T cell engagers necessitates continuous intravenous administration at high doses for four weeks at a time. Given their ability to produce proteins at steady state, BCMs are particularly well-suited to overcome these pharmacokinetic shortcomings. To generate BCMs, B cells are engineered ex vivo to constitutively secrete transgenic biologics and then differentiated into plasma cells. These cells were chosen for their high antibody production capacity (thousands of Ig molecules/cell/sec) and ability to engraft without preconditioning, making them a highly attractive cell-based platform for continuous biologic delivery1.

About the Study

To demonstrate proof-of-concept, a transgene coding for a bispecific anti-CD3:CD19 scFv was integrated into a safe-harbor locus of primary human B cells via targeted gene knock in. The engineered B cells were then differentiated into plasma cells ex vivo. Assessment of in vivo anti-tumor activity of these BCMs was conducted in NSG mice harboring a patient-derived CD19-expressing xenograft (PDx). Mice were inoculated with a luciferized B-ALL PDx line and autologous T cells were delivered after tumor transfer. Significant reduction in tumor burden (bioluminescent flux, area under the curve) was observed over the course of the 17-day study in the anti-CD3:CD19 scFv cohort compared to controls, which was in concordance with heightened in vivo T cell activation. The ~1000 pg/mL bispecific T cell engagers detected in mouse plasma demonstrated that a BCM-derived biologic can meet or even exceed the steady-state plasma concentrations achieved with clinically relevant blinatumomab doses2.

Deidentified human PBMCs were acquired under informed consent from the Fred Hutch Specimen Processing and Research Cell Bank (protocol #3942).

No toxicities were identified in this study.

About Engineered B Cell Medicines – 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.