Ex vivo engineered human plasma cells exhibit robust protein secretion and long-term engraftment in vivo

Abstract

Due to their unique longevity and capacity to secrete high levels of protein, plasma B cells have the potential to be used as a cell therapy for protein replacement. Here, we show that ex vivo engineered human plasma cells exhibit single-cell RNA profiles, scanning electron micrograph ultrastructural features, and in vivo homing capacity of long-lived plasma cells. After transferring human plasma cells to immunodeficient mice in the presence of the human cytokines BAFF and IL-6, we observe increases in retention of plasma cells in the bone marrow, with engraftment exceeding a year. The most profound in vivo effects of human IL-6 are observed within 20 days of transfer and could be explained by decreased apoptosis in newly differentiated plasma cells. Collectively, these results show that ex vivo engineered and differentiated human plasma cells have the potential for long-lived in vivo protein secretion, which can be modeled in small animals.

A lentiviral vector B cell gene therapy platform for the delivery of the anti-HIV-1 eCD4-Ig-knob-in-hole-reversed immunoadhesin

“…B cells have appealing features for gene engineering to produce therapeutic proteins; they differentiate into long-lived memory and plasma cells capable of robust and long-term antibody production and migrate to lymphoid, bone marrow, and vascular compartments. 36 , 59 , 73 LV-based delivery, if made efficient via pseudotyping to target B cells, 44 , 45 , 46 , 47 is predicted to mediate sustained, high-level therapeutic protein expression and is capable of delivering a large therapeutic payload(s) to transduced primary B cells. As described previously, our findings demonstrate that VSV-G pseudotyped LV vectors mediate only minimal transduction of activated primary human B cells.…”

“…Additional support for future engineered B cell studies in humanized mice comes from our studies showing that eCD4-Ig AAV-mediated direct delivery to non-human primate myocytes controls SHIV challenge for a time 32 and our recent report that ex vivo engineered human plasma cells home and function when transplanted to humanized mice. 36 …”

“… 35 In addition, we have found that engineered plasma B cells migrate to secondary lymphoid organs in the body and can produce localized proteins in situ for longer than 1 year. 36 Upon activation, B cells can differentiate into long-lived plasma cells that secrete large quantities of antibodies, making them an excellent candidate for gene-therapy-mediated immunotherapy approaches. 37 , 38 , 39 B cells also provide a promising approach for active immunotherapy against pathogens, such as HIV-1, given their ability to secrete high quantities of antibody and to migrate into most tissues.…”

Reprogramming human B cells with custom heavy-chain antibodies

“…43 They therefore have the potential to act as in vivo factories, secreting both antibodies and non-antibody proteins. 34,44 B cells also form memory cells, an antigen-responsive population that is at least as long-lived as plasma cells. 45 Memory B cells may play an important role in immune responses in tissues, including the lung mucosa and solid tumors, 46,47 and can also re-seed the plasma cell compartment in response to repeat antigen exposure.…”

Therapeutic tactics for targeting B lymphocytes in autoimmunity and cancer

“…On the horizon of medical discovery, we see the potential for B cells to be deployed in cell-based, protein-delivery-style therapies. Recent work from Seattle Children's Research Institute's Center for Immunity and Immunotherapies demonstrates the ability to engraft human plasma cells into immunodeficient mice for over a year [147]. The natural ability of plasma cells to produce and secrete antibodies makes them an intriguing candidate as a cellular protein delivery therapeutic.…”