Engineered B cells for Novel Cell Therapies
Genome-editing B cells for in vivo delivery of antibodies and other therapeutic proteins
Technology Overview
Plasma B cells persist for years and can secrete large amounts of antibody, estimated at thousands of molecules per second. These features make plasma B cells an ideal system for in vivo delivery of therapeutic protein drugs. These drug-secreting B cells could be used to treat patients with diseases requiring protein replacement therapy, such as hemophilia, cancer, or autoimmunity.
Development of a B cell-based cell therapy has been limited by the lack of efficient engineering methods for these cells. Dr. Richard James leads a team of researchers who have overcome this limitation. The team developed methods for high-efficiency genome editing of human primary B cells from blood samples.
Dr. Richard James
Plasma B cells persist for years and can secrete large amounts of antibody, estimated at thousands of molecules per second. These features make plasma B cells an ideal system for in vivo delivery of therapeutic protein drugs. These drug-secreting B cells could be used to treat patients with diseases requiring protein replacement therapy, such as hemophilia, cancer, or autoimmunity.
Development of a B cell-based cell therapy has been limited by the lack of efficient engineering methods for these cells. Dr. Richard James leads a team of researchers who have overcome this limitation. The team developed methods for high-efficiency genome editing of human primary B cells from blood samples.
Dr. James and colleagues are also experienced in differentiating the engineered primary cells, expanding the population of mature B cells, and engrafting them into mouse models. They have used this expertise to demonstrate that engineered drug-secreting B cells exhibit longevity and a high capacity to secrete therapeutic proteins. These proof-of-concept studies support the clinical potential of genome-edited B cells.
The group engineered plasma B cells to secrete high levels of factor IX, the clotting factor that is currently provided by infusion to patients with hemophilia. They also generated plasma cells that produce B cell activating factor (BAFF), a protein that can directly modulate B cell differentiation and function. Engineered cells that are differentiated and engrafted into immunodeficient mice are stable in vivo and secrete engineered proteins for at least 1 year. In addition to replacement proteins and immune-modulating factors, the system could be used to administer vaccine proteins or consistently deliver therapeutic antibodies, potentially for a lifetime.\
Dr. James and colleagues continue to refine their diverse genome-editing methods. Their system is capable of multiplex editing or altering single genes. Delivery options include specially designed adeno-associated viruses and direct delivery of CRISPR/Cas9 ribonucleoproteins. The team also has experience with other genome-editing systems such as zinc-finger nucleases, TALENs, and megaTALs. In the team’s hands, CRISPR-based editing is highly efficient, with at least 90% gene disruption and 40% gene integration by homology-directed repair.
Dr. James also has expertise in quantitative proteomics and mass spectrometry. He is especially interested in partnerships that can advance B cell engineering to develop novel cell therapies.
Stage of Development
- Pre-clinical in vitro, in vivo, ex vivo
- Clinical trials
Partnering Opportunities
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Collaborative animal model development
Publications
- Hung KL, Meitlis I, Hale M, Chen CY, Sing S, Jackson SW, Miao CH, Khan IF, Rawlings DJ and James RG. Engineering protein-secreting plasma cells by homology-directed repair in primary human B cells. Mol Ther. 2018; 26(2):456-67.
- Wray-Dutra MN, Al Qureshah F, Metzler G, Oukka M, James RG, Rawlings DJ. Activated PIK3CD drives innate B cell expansion yet limits B cell-intrinsic immune responses. J Exp Med. 2018;215(10):2485-2496. doi: 10.1084/jem.20180617.
- Wray-Dutra MN, Chawla R, Thomas KR, Seymour BJ, Arkatkar T, Sommer KM, Khim S, Trapnell C, James RG, Rawlings DJ. Activated CARD11 accelerates germinal center kinetics, promoting mTORC1 and terminal differentiation. J Exp Med. 2018;215(9):2445-2461. doi: 10.1084/jem.20180230.
- Dam EM, Habib T, Chen J, Funk A, Glukhova V, Davis-Pickett M, Wei S, James RG, Buckner JH, Cerosaletti K. The BANK1 SLE-risk variants are associated with alterations in peripheral B cell signaling and development in humans. Clin Immunol. 2016;173:171-180.
- Tampella G, Kerns HM, Niu D, Singh S1, Khim S...James RG. The Tec Kinase-Regulated Phosphoproteome Reveals a Mechanism for the Regulation of Inhibitory Signals in Murine Macrophages. J Immunol.2015; 195:246-56. doi: 10.4049
Learn More
To learn more about partnering with Seattle Children’s Research Institute on this or other projects, email the Office of Science-Industry Partnerships.