OC 11.3 - Development of BE-101, an autologous ex vivo precision gene engineered B cell medicine that produces active and sustained levels of factor IX for the treatment of hemophilia B

Sunday, June 23, 2024

10:00 – 10:15 ICT

Room: Ballroom B1

Presenting Author(s)

Wing Yen Wong, MD

Chief Medical Officer
Be Biopharma
San Francisco, California, United States

Co-Author(s)

HL

Hanlan Liu

SVP, Early Pipeline and Nonclinical Development
Be Biopharma
Cambridge, Massachusetts, United States
SS

Swati Singh

Principal Scientist, Cell Biology
Be Biopharma
Cambridge, Massachusetts, United States
TM

Timothy Mullen

Senior Scientist, B Cell Engineering
Be Biopharma
Cambridge, Massachusetts, United States
CB

Caroline Bullock

Principal In Vivo Pharmacologist
Be Biopharma
Cambridge, Massachusetts, United States
SK

Sean Keegan

Senior Principal Scientist
Be Biopharma
Cambridge, Massachusetts, United States
TP

Troy Patterson

Senior Scientist, In Vivo Pharmacology
Be Biopharma
Cambridge, Massachusetts, United States
AL

Amy Lundberg

Scientist, Translational Biology
Be Biopharma
Cambridge, Massachusetts, United States
ST

Sakshisingh Thakur

Associate Scientist, B Cell Engineering
Be Biopharma
Cambridge, Massachusetts, United States
CY

Charuta Yadav

Associate Scientist, Translational Biology
Be Biopharma
Cambridge, Massachusetts, United States
SD

Shamael Dastagir

Scientist II, Bioassay Development
Be Biopharma
Cambridge, Massachusetts, United States
LL

Lily Li

Senior Associate Scientist, Bioassay Development
Be Biopharma
Cambridge, Massachusetts, United States
WB

Wayne Bainter

Scientist, Rare Disease
Be Biopharma
Cambridge, Massachusetts, United States
SC

Shalini Chilakala

Director, Bioanalysis
Be Biopharma
Cambridge, Massachusetts, United States
AH

Anja Hohmann

Senior Director, Cell Engineering
Be Biopharma
Cambridge, Massachusetts, United States
AL

Adam Lazorchak

Director, In Vivo Pharmacology
Be Biopharma
Cambridge, Massachusetts, United States
CS

Chris Scull

Head Nonclinical Development
Be Biopharma
Washington, District of Columbia, United States
RM

Richard Morgan

Chief Scientific Officer
Be Biopharma
Cambridge, Massachusetts, United States

Background: Despite advances in treatment options for hemophilia B, significant unmet needs remain, notably disease and treatment burden.

Aims: Terminally differentiated human plasma cells derived from genetically engineered B Cell Medicines (BCMs), potentially offer natural longevity (average half-life up to 17 years), capacity for high levels of protein secretion, ability to engraft without host preconditioning, and re-dosability, thus makes them an attractive platform to provide durable and long-lasting effects in adolescents and children as well as adults.

Methods: In this study, primary human B cells were isolated, activated, and engineered by CRISPR/Cas9 genome editing followed by AAV-mediated homology directed repair insertion of human F9 gene into the C-C chemokine receptor type 5 (CCR5) safe harbor locus. The cells were then further expanded and differentiated towards the plasma cell lineage, resulting in FIX-producing BCMs.

Results: Engineered BCMs secreted up to 60 ng/1e6 cells/hour of FIX protein. BCM-produced FIX analyzed by LC-MS demonstrated gamma carboxylation of FIX protein Gal-domain. Vitamin K-dependent activated partial thromboplastin time (aPTT) using the one stage clotting and immunocapture chromogenic assays (left Figure), were employed to verify biological activity of BCM-produced FIX. FIX-expressing BCMs were transferred into immunodeficient NOG-hIL6 mice, with FIX production demonstrated at least 168 days (right Figure). There were no FIX-producing BCMs related safety findings. GLP toxicology and off-target evaluation studies are on-going with no concerns identified to date.

Conclusion(s): In summary, we have developed an ex vivo precision gene engineered B cell medicine that produces active and sustained levels of FIX for the treatment of hemophilia B (BE-101). We are rapidly moving toward clinical application and in anticipation of the first-in-human clinical trial in 2024 for people with moderately severe to severe hemophilia B.