Autoantibody depletion ameliorates disease in murine experimental autoimmune encephalomyelitis

Challa, Dilip K.; Bussmeyer, Uta; Khan, Tarique; Montoyo, Héctor Pérez; Bansal, Pankaj; Ober, Raimund J.; Ward, E. Sally

doi:10.4161/mabs.25439

Cited by 48 publications

(54 citation statements)

References 38 publications

(43 reference statements)

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“…If the Ab pool participates in driving EAE severity, EAE mice that have undergone CD19 mAb treatment should develop EAE when serum from EAE mice induced with rhMOG is passively transferred into them. Others have demonstrated the potent capacity of anti-MOG Abs to confer EAE in other models (4,5,15,17), albeit not CD19 mAb-treated mice. We further identified that CD19 + CD20 2 ASCs were specifically targeted by CD19 mAb but not CD20 mAb, which potentially harbors autoreactivity (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the CD19 mAb was more effective than the CD20 mAb in suppressing EAE progression (Fig. 1A, CD19 mAb versus CD20 mAb, p , 0.05, days [15][16][17][20][21][22][23][24][25][26][27]. In a separate experiment, we found that neither control Abs (16C4-TM, a control for CD19 mAb, and 6.3, a control for CD20 mAb) influenced EAE progression when the mice were treated with a single 250-mg dose at day 7 after rhMOG immunization (Supplemental Fig.…”

Section: Cd19 Mab Is More Effective Than Cd20 Mab In Suppressing Eaementioning

confidence: 97%

“…These autoantibody-secreting long-lived PCs are extremely refractory to conventional immunosuppressive therapies, including biologics such as B cell depletion regimens (17)(18)(19)(20). There is some evidence suggesting that the sparing of long-lived PCs is due to their lack of expression of CD20, which is the target of current B cell depletion therapies such as rituximab (1,21).…”

Section: G Rowing Evidence Suggests That B Cells and Abs Play An Impomentioning

confidence: 99%

“…In agreement with the disease score, CD19 mAb-treated mice showed accelerated improvement compared with the CD20 mAb-treated mice (p , 0.05 for forelimbs from day 16 to day 24; p , 0.05 for hindlimbs from day 15 to day 28). Specifically, CD19 mAb-treated mice showed significant recovery of strength for both forelimbs (p , 0.05, days [16][17][18][19][20][21][22][23][24][25][26] and hindlimbs (p , 0.05, days 18-28) compared with the PBS group. In contrast, CD20 mAb-treated mice only showed strength improvement at three single time points along the disease course for forelimbs (p , 0.05, days 18, 19, and 23) and one single time point for hindlimbs (p , 0.05, day 19) compared with the PBS group.…”

Section: Cd19 Mab Is More Effective Than Cd20 Mab In Suppressing Eaementioning

confidence: 99%

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Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

Chen

Ireland

Davis

et al. 2016

The Journal of Immunology

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The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody-producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein–specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb–treated mice, but they remained detectable in the CD20 mAb–treated mice. Interestingly, residual disease severity in the CD20 mAb–treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19+CD20− plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19+CD20− plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19+CD20− B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Cd19 Mab Is More Effective Than Cd20 Mab In Suppressing Eaementioning

confidence: 97%

Section: G Rowing Evidence Suggests That B Cells and Abs Play An Impomentioning

confidence: 99%

Section: Cd19 Mab Is More Effective Than Cd20 Mab In Suppressing Eaementioning

confidence: 99%

See 2 more Smart Citations

Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

Chen

Ireland

Davis

et al. 2016

The Journal of Immunology

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“…This has been demonstrated to be the case for a human IgG1 (hIgG1) mutant with five substitutions in the Fc (M252Y/S254T/T256E/H433K/N434F; MST/ HN), denoted as Abs for degradation. However, the mutant has shown promise as an FcRn blocker that accelerates the clearance of pathogenic IgG in mouse models (34,39,40).…”

mentioning

confidence: 99%

Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

Grevys

Bern

Foss

et al. 2015

The Journal of Immunology

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Engineering of the constant Fc part of monoclonal human IgG1 (hIgG1) Abs is an approach to improve effector functions and clinical efficacy of next-generation IgG1-based therapeutics. A main focus in such development is tailoring of in vivo half-life and transport properties by engineering the pH-dependent interaction between IgG and the neonatal Fc receptor (FcRn), as FcRn is the main homeostatic regulator of hIgG1 half-life. However, whether such engineering affects binding to other Fc-binding molecules, such as the classical FcγRs and complement factor C1q, has not been studied in detail. These effector molecules bind to IgG1 in the lower hinge–CH2 region, structurally distant from the binding site for FcRn at the CH2–CH3 elbow region. However, alterations of the structural composition of the Fc may have long-distance effects. Indeed, in this study we show that Fc engineering of hIgG1 for altered binding to FcRn also influences binding to both the classical FcγRs and complement factor C1q, which ultimately results in alterations of cellular mechanisms such as Ab-dependent cell-mediated cytotoxicity, Ab-dependent cellular phagocytosis, and Ab-dependent complement-mediated cell lysis. Thus, engineering of the FcRn–IgG1 interaction may greatly influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIgG1 variants.

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Engineering Antibody‐Based Therapeutics: Progress and Opportunities

Nguyen

Maynard

2021

Protein Engineering

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Autoantibody depletion ameliorates disease in murine experimental autoimmune encephalomyelitis

Cited by 48 publications

References 38 publications

Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

Autoreactive CD19+CD20− Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis

Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

Engineering Antibody‐Based Therapeutics: Progress and Opportunities

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