A nondepleting anti-CD19 antibody impairs B cell function and inhibits autoimmune diseases

Boyles, Jeffrey S.; Sadowski, Dorota; Potter, Scott C.; Vukojicic, Aleksandra; Parker, James; Chang, William Y.; Li, Yanfei; Chambers, M.G.; Nelson, James; Barmettler, Barbra; Smith, Eric M.; Kersjes, Kara; Himes, Evan R.; Lin, Chaohua; Lucchesi, Jonathan; Brahmbhatt, Jaladhi; Ramtin, Sina; Martin, Jennifer A.; Maestri, Evan; Wiethoff, Christopher M.; Dyas, Gregory L.; Linnik, Matthew D.; Na, Songqing; Witcher, Derrick R.; Budelsky, Alison; Rubtsova, Kira

doi:10.1172/jci.insight.166137

Cited by 4 publications

(3 citation statements)

References 47 publications

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“…This suggests targeting CD19 may have more advantages than targeting CD20. In line with this, a non-depleting antibody LY3541860 potently inhibited B cell function and showed superior activity in the inhibition of disease severity in a TD1 mouse model, compared to anti-CD20 29 .…”

Section: Discussionmentioning

confidence: 63%

Targeting CD19 for the treatment of autoimmune with a novel T cell engager

Yuan,

Zhao,

Bai

et al. 2024

Preprint

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Autoimmune disorder, affecting more than twenty million in United States and billions of people worldwide, occurs when human immune system mistakenly attacks its own body. Autoreactive B cells, particularly the autoantibodies they produce, play a critical role in the etiology, progress, prognosis, and pathogenesis of multiple autoimmune diseases. While targeting B cells medicines, especially anti-CD19 or anti-CD20 monoclonal antibodies showed promise in both pre-clinic models and some clinic practices, many patients failed to respond or relapsed to monoclonal antibody therapies. Novel therapy is desperately needed to fight this challenge. In this study, a novel designed anti-CD19xCD3 T cell engager (TCE), named 19K3, developed to cure precursor pre-B acute lymphatic leukemia and non-Hodgkin’s lymphoma, was repurposed to bring T cells to CD19 positive B cells for treatment of autoimmune diseases. 19K3 has so significantly reduced binding affinity to CD3 compared to its parental clone that even as bivalent binding to TCR, free 19K3 alone does activate T cells. In contrast, in the presence of CD19 positive Raji target cells and mediated by 19K3, human T cells can be activated in a dose-dependent manner measured by upregulation of CD25, IFN-γ and granzyme B expression. As an engager, crosslinking of B cell with T cell by 19K3, the conjugation elicited T cell-mediated cytotoxicity only to CD19-positive Raji cells but not CD19-negative MV-4-11 cells. More interestingly, 19K3 induced much reducedin vitrocytokines release compared to that of Blincyto biosimilar, implying to be a potentially me-better therapeutics replacement in clinics for B-cell related diseases. In summary, this study demonstrated that by novel designing, an anti-CD3xCD19 TCE, 19K3 harnesses cytolytic T cells to eradicate B cells has the potential to treat B cell-mediated autoimmune diseases with better efficacy and less side effects.

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Section: Discussionmentioning

confidence: 63%

Targeting CD19 for the treatment of autoimmune with a novel T cell engager

Yuan,

Zhao,

Bai

et al. 2024

Preprint

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“…MS4A1 is thought to function for B cell activation, proliferation, and differentiation and is associated with a variety of B cell surface molecules [ 50 , 51 , 52 ]. It is expressed during B cell differentiation from pre-B cells to the stage of plasmablasts, while CD19 molecules start at the late pro-B cell stage (prior to the expression of MS4A1) and are maintained throughout B cell activation until differentiation into plasma cells when CD19 expression is partially or completely lost [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

“…Inebilizumab (UPLIZNA ® , mAbID 553 ), a humanized antibody that binds and depletes B-cells that express CD19 molecule [ 62 ], is in phase III clinical trial with approximately 270 participants and an estimated completion date by the end of 2024 (NCT04524273) [ 63 ]. Inebilizumab targets and binds to CD19 antigen, which is continuously and stably expressed on all stages of B lineage differentiation on the surface of B cell lymphocytes [ 53 ]. Once bound to CD19, inebilizumab depletes circulating CD19+ B cells, thus suppressing inflammatory responses and impairing B-cell-dependent T-cell activation.…”

Section: Resultsmentioning

confidence: 99%

Delving into Molecular Pathways: Analyzing the Mechanisms of Action of Monoclonal Antibodies Integrated in IMGT/mAb-DB for Myasthenia Gravis

Golfinopoulou,

Giudicelli,

Manso

et al. 2023

Vaccines

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Background: Myasthenia Gravis (MG) is a rare autoimmune disease presenting with auto-antibodies that affect the neuromuscular junction. In addition to symptomatic treatment options, novel therapeutics include monoclonal antibodies (mAbs). IMGT®, the international ImMunoGeneTics information system®, extends the characterization of therapeutic antibodies with a systematic description of their mechanisms of action (MOA) and makes them available through its database for mAbs and fusion proteins, IMGT/mAb-DB. Methods: Using available literature data combined with amino acid sequence analyses from mAbs managed in IMGT/2Dstructure-DB, the IMGT® protein database, biocuration allowed us to define in a standardized way descriptions of MOAs of mAbs that target molecules towards MG treatment. Results: New therapeutic targets include FcRn and molecules such as CD38, CD40, CD19, MS4A1, and interleukin-6 receptor. A standardized graphical representation of the MOAs of selected mAbs was created and integrated within IMGT/mAb-DB. The main mechanisms involved in these mAbs are either blocking or neutralizing. Therapies directed to B cell depletion and plasma cells have a blocking MOA with an immunosuppressant effect along with Fc-effector function (MS4A1, CD38) or FcγRIIb engager effect (CD19). Monoclonal antibodies targeting the complement also have a blocking MOA with a complement inhibitor effect, and treatments targeting T cells have a blocking MOA with an immunosuppressant effect (CD40) and Fc-effector function (IL6R). On the other hand, FcRn antagonists present a neutralizing MOA with an FcRn inhibitor effect. Conclusion: The MOA of each new mAb needs to be considered in association with the immunopathogenesis of each of the subtypes of MG in order to integrate the new mAbs as a viable and safe option in the therapy decision process. In IMGT/mAb-DB, mAbs for MG are characterized by their sequence, domains, and chains, and their MOA is described.

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Non-depleting anti-CD19 B cell inhibition

Phillips

2023

Nat Rev Rheumatol

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A nondepleting anti-CD19 antibody impairs B cell function and inhibits autoimmune diseases

Cited by 4 publications

References 47 publications

Targeting CD19 for the treatment of autoimmune with a novel T cell engager

Targeting CD19 for the treatment of autoimmune with a novel T cell engager

Delving into Molecular Pathways: Analyzing the Mechanisms of Action of Monoclonal Antibodies Integrated in IMGT/mAb-DB for Myasthenia Gravis

Non-depleting anti-CD19 B cell inhibition

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