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

Vamva, Eirini; Ozog, Stosh; Leaman, Daniel P.; Cheng, Rene Yu-Hong; Irons, Nicholas J.; Ott, Andee R.; Stoffers, Claire M.; Khan, Iram; Goebrecht, Geraldine K.E.; Gardner, Matthew R.; Farzan, Michael; Rawlings, David J.; Zwick, Michael B.; James, Richard G.; Torbett, Bruce E.

doi:10.1016/j.omtm.2023.02.004

Cited by 8 publications

(8 citation statements)

References 98 publications

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“…Of note, the authors reported unwanted cleavage of off-target genome sites with this approach, albeit at low frequency [114]. Finally, of significant note is the lentiviral-mediated B cell transduction strategy reported recently by Vamva et al [115] to express the eCD4-Ig immunoadhesin. Through the use of an optimized lentivirus containing the B cell-specific promoter EμB29, the authors achieved efficient expression of this protein in human B cells, capable of neutralizing HIV in vitro .…”

Section: Introductionmentioning

confidence: 91%

“…Through the use of an optimized lentivirus containing the B cell-specific promoter EμB29, the authors achieved efficient expression of this protein in human B cells, capable of neutralizing HIV in vitro . Further studies are needed to test the feasibility of this approach in vivo and its protection efficacy [115]. While significantly less mature than other platforms, the field of B cell engineering is making rapid advances towards clinical translation of these technologies.…”

Section: Introductionmentioning

confidence: 99%

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Delivery platforms for broadly neutralizing antibodies

Joshi

Gálvez

Ghosh

et al. 2023

Current Opinion in HIV and AIDS

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Purpose of reviewPassive administration of broadly neutralizing antibodies (bNAbs) is being evaluated as a therapeutic approach to prevent or treat HIV infections. However, a number of challenges face the widespread implementation of passive transfer for HIV. To reduce the need of recurrent administrations of bNAbs, gene-based delivery approaches have been developed which overcome the limitations of passive transfer.Recent findingsThe use of DNA and mRNA for the delivery of bNAbs has made significant progress. DNA-encoded monoclonal antibodies (DMAbs) have shown great promise in animal models of disease and the underlying DNA-based technology is now being tested in vaccine trials for a variety of indications. The COVID-19 pandemic greatly accelerated the development of mRNA-based technology to induce protective immunity. These advances are now being successfully applied to the delivery of monoclonal antibodies using mRNA in animal models. Delivery of bNAbs using viral vectors, primarily adeno-associated virus (AAV), has shown great promise in preclinical animal models and more recently in human studies. Most recently, advances in genome editing techniques have led to engineering of monoclonal antibody expression from B cells. These efforts aim to turn B cells into a source of evolving antibodies that can improve through repeated exposure to the respective antigen.SummaryThe use of these different platforms for antibody delivery has been demonstrated across a wide range of animal models and disease indications, including HIV. Although each approach has unique strengths and weaknesses, additional advances in efficiency of gene delivery and reduced immunogenicity will be necessary to drive widespread implementation of these technologies. Considering the mounting clinical evidence of the potential of bNAbs for HIV treatment and prevention, overcoming the remaining technical challenges for gene-based bNAb delivery represents a relatively straightforward path towards practical interventions against HIV infection.

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Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Delivery platforms for broadly neutralizing antibodies

Joshi

Gálvez

Ghosh

et al. 2023

Current Opinion in HIV and AIDS

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“…Challenges to B cell medicine approaches include inefficient transducOon, achieving protein producOon at a level likely to be therapeuOc, and manufacturing at scale. 20 However, recent breakthroughs in B cell ediOng 14,[21][22][23][24] using CRISPR/Cas9 coupled with adeno-associated virus mediated delivery of a homology directed repair template enables the efficient introducOon of transgenes into safe-harbor loci (e.g., CCR5) or the immunoglobulin locus. [22][23][24][25] Advances have also been seen with lenOviral systems.…”

Section: Introductionmentioning

confidence: 99%

“…[22][23][24][25] Advances have also been seen with lenOviral systems. 21 These techniques produce stable expression at levels predicted to be clinically significant. [25][26][27] Furthermore, xenotransplant models confirm that edited human plasma cells derived from ex vivo expanded B cells can be detected for up to a year following infusion and conOnue to produce human immunoglobulins detectable in the plasma.…”

Section: Introductionmentioning

confidence: 99%

In vivotracking ofex vivogenerated⁸⁹Zr-oxine labeled plasma cells by PET in a non-human primate model

Young,

Edwards,

Quiroz Caceda

et al. 2024

Preprint

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B cells are an attractive platform for engineering to produce protein-based biologics absent in genetic disorders, and potentially for the treatment of metabolic diseases and cancer. As part of pre-clinical development of B cell medicines, we demonstrate a method to collect,ex vivoexpand, differentiate, radioactively label, and track adoptively transferred non-human primate (NHP) B cells. These cells underwent 10- to 15-fold expansion, initiated IgG class switching, and differentiated into antibody secreting cells. Zirconium-89-oxine labeled cells were infused into autologous donors without any preconditioning and tracked by PET/CT imaging. Within 24 hours of infusion, 20% of the initial dose homed to the bone marrow and spleen and distributed stably and equally between the two. Interestingly, approximately half of the dose homed to the liver. Image analysis of the bone marrow demonstrated inhomogeneous distribution of the cells. The subjects experienced no clinically significant side effects or laboratory abnormalities. A second infusion of B cells into one of the subjects resulted in an almost identical distribution of cells, suggesting a non-limiting engraftment niche and feasibility of repeated infusions. This work supports the NHP as a valuable model to assess the potential of B cell medicines as potential treatment for human diseases.

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“…Recently, we developed a cell-based method to deliver protein drugs, which we have successfully tested in immune-deficient mice. To do this, we generated ex vivo differentiated human plasma cells (PCs) and engineered them to produce protein drugs (including bispecific antibodies), and in immuno-deficient mice, we observed long-lasting antibody secretion for a year and potent tumor killing [1][2][3][4] .…”

Section: Introductionmentioning

confidence: 99%

Advancing Cell Therapies: Single-Cell Profiling, Generation, Expansion, and Gene Delivery in Rhesus Macaque Plasma B Cells

Cheng,

Kreuser,

Dahl

et al. 2023

Preprint

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Engineered long lived plasma cells have the potential to be a new area of cell therapy. A key step in developing this cell therapy is testing in a model with an intact immune system similar to humans. To that end, we have developed methods to purify, expand, and differentiate non-human primate (NHP;rhesus macaque) B cellsex vivo. We consistently achieved 10-fold expansion of NHP B cells using a readily available commercial supplement. After only seven days in culture, large percentages of cells in NHP B cell cultures were differentiated. These cells expressed surface markers found in human antibody secreting cells (CD38 and CD138) and secreted immunoglobulin G. From single cell transcriptome analysis of NHP, we verified the presence of plasma cell markers commonly shared with humans, and have unearthed less recognized markers such asCD59and CD79A. In addition, we identified unique NHP plasma cell markers that are absent in humans including the immune checkpoint moleculeCD274(PD-L1, Programmed Death-Ligand 1). Furthermore, we found that MHC class I molecules were upregulated in NHP plasma cells, in contrast to the pattern observed in humans. Lastly, we also identified the serotypes (AAVD-J) and established the conditions for efficient transduction of NHP B cells with AAV vectors, achieving an editing rate of approximately 60%. We envision that this work will accelerate proof-of-conceptin vivostudies using engineered protein-secreting B cells in the NHP model.

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

Cited by 8 publications

References 98 publications

Delivery platforms for broadly neutralizing antibodies

Delivery platforms for broadly neutralizing antibodies

In vivotracking ofex vivogenerated⁸⁹Zr-oxine labeled plasma cells by PET in a non-human primate model

Advancing Cell Therapies: Single-Cell Profiling, Generation, Expansion, and Gene Delivery in Rhesus Macaque Plasma B Cells

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

Cited by 8 publications

References 98 publications

Delivery platforms for broadly neutralizing antibodies

Delivery platforms for broadly neutralizing antibodies

In vivotracking ofex vivogenerated89Zr-oxine labeled plasma cells by PET in a non-human primate model

Advancing Cell Therapies: Single-Cell Profiling, Generation, Expansion, and Gene Delivery in Rhesus Macaque Plasma B Cells

Contact Info

Product

Resources

About

In vivotracking ofex vivogenerated⁸⁹Zr-oxine labeled plasma cells by PET in a non-human primate model