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Non-depleting anti-CD4 monoclonal antibody induces immune tolerance to ERT in a murine model of Pompe disease

View Article: PubMed Central - PubMed

ABSTRACT

Approximately 35–40% of patients with classic infantile Pompe disease treated with enzyme replacement therapy (ERT) develop high, sustained antibody titers against the therapeutic enzyme alglucosidase alfa, which abrogates the treatment efficacy. Induction of antigen-specific immune tolerance would greatly enhance ERT for these patients. Here we show that a short-course treatment with non-depleting anti-CD4 monoclonal antibody successfully induced long-term ERT-specific immune tolerance in Pompe disease mice. Our data suggest an effective adjuvant therapy to ERT.

No MeSH data available.


ELISA for anti-hGAA IgG antibody in GAA-KO mice under weekly ERT with 20 mg/kg of rhGAA. The antibody levels were presented by the absorbance for 1:200 dilution of plasma from the indicated groups of mice. Mean plus standard deviation  is shown, n = 10 for each group. (A) Both the 3-dose anti-CD4 mAb (anti-CD4x3 group) and methotrexate treatments significantly (p < 0.05) reduced rhGAA antibody levels in the GAA-KO mice after 4 weeks of rhGAA treatment in comparison with the control mice (ERT only). (B) A 2-dose treatment (anti-CD4x2 group) was similarly effective in inhibiting anti-rhGAA antibody formation as the 3-dose regimen (anti-CD4x3 group), but a single-dose treatment (anti-CD4x1 group) failed to significantly (p > 0.05) reduce the anti-rhGAA antibody levels, in comparison to the control group.
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f0005: ELISA for anti-hGAA IgG antibody in GAA-KO mice under weekly ERT with 20 mg/kg of rhGAA. The antibody levels were presented by the absorbance for 1:200 dilution of plasma from the indicated groups of mice. Mean plus standard deviation  is shown, n = 10 for each group. (A) Both the 3-dose anti-CD4 mAb (anti-CD4x3 group) and methotrexate treatments significantly (p < 0.05) reduced rhGAA antibody levels in the GAA-KO mice after 4 weeks of rhGAA treatment in comparison with the control mice (ERT only). (B) A 2-dose treatment (anti-CD4x2 group) was similarly effective in inhibiting anti-rhGAA antibody formation as the 3-dose regimen (anti-CD4x3 group), but a single-dose treatment (anti-CD4x1 group) failed to significantly (p > 0.05) reduce the anti-rhGAA antibody levels, in comparison to the control group.

Mentions: The initial experiment showed that mice in the control group generated high levels of anti-rhGAA antibody that started increasing from 2 weeks, peaked at 16 weeks ((absorbance = 0.225) and then declined remaining consistently above 0.13 level after 24 weeks (Fig. 1A). Both the methotrexate (MTX group) and 3-dose anti-CD4 mAb (anti-CD4x3 group) treated groups showed significantly (p < 0.05) decreased anti-rhGAA antibody levels after 4 weeks of rhGAA treatment when compared to the control group (Fig. 1A). The overall antibody levels for the anti-CD4x3 group remained lower than those of the MTX group throughout the 28-week treatment with rhGAA. Comparing the area under the curve, the anti-CD4x3 group and the MTX group showed a 94.3% and 84.5% reduction of antibody levels, respectively, as compared to the control group (Fig. 1A). Rechallenge with rhGAA at 40 weeks did not significantly change the antibody levels in any of the 3 groups (Fig. 1A). The serum anti-CD4 mAb levels in the anti-CD4x3 group continuously decreased after administration and remained undetectable after 23 weeks (data not shown).


Non-depleting anti-CD4 monoclonal antibody induces immune tolerance to ERT in a murine model of Pompe disease
ELISA for anti-hGAA IgG antibody in GAA-KO mice under weekly ERT with 20 mg/kg of rhGAA. The antibody levels were presented by the absorbance for 1:200 dilution of plasma from the indicated groups of mice. Mean plus standard deviation  is shown, n = 10 for each group. (A) Both the 3-dose anti-CD4 mAb (anti-CD4x3 group) and methotrexate treatments significantly (p < 0.05) reduced rhGAA antibody levels in the GAA-KO mice after 4 weeks of rhGAA treatment in comparison with the control mice (ERT only). (B) A 2-dose treatment (anti-CD4x2 group) was similarly effective in inhibiting anti-rhGAA antibody formation as the 3-dose regimen (anti-CD4x3 group), but a single-dose treatment (anti-CD4x1 group) failed to significantly (p > 0.05) reduce the anti-rhGAA antibody levels, in comparison to the control group.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5121343&req=5

f0005: ELISA for anti-hGAA IgG antibody in GAA-KO mice under weekly ERT with 20 mg/kg of rhGAA. The antibody levels were presented by the absorbance for 1:200 dilution of plasma from the indicated groups of mice. Mean plus standard deviation  is shown, n = 10 for each group. (A) Both the 3-dose anti-CD4 mAb (anti-CD4x3 group) and methotrexate treatments significantly (p < 0.05) reduced rhGAA antibody levels in the GAA-KO mice after 4 weeks of rhGAA treatment in comparison with the control mice (ERT only). (B) A 2-dose treatment (anti-CD4x2 group) was similarly effective in inhibiting anti-rhGAA antibody formation as the 3-dose regimen (anti-CD4x3 group), but a single-dose treatment (anti-CD4x1 group) failed to significantly (p > 0.05) reduce the anti-rhGAA antibody levels, in comparison to the control group.
Mentions: The initial experiment showed that mice in the control group generated high levels of anti-rhGAA antibody that started increasing from 2 weeks, peaked at 16 weeks ((absorbance = 0.225) and then declined remaining consistently above 0.13 level after 24 weeks (Fig. 1A). Both the methotrexate (MTX group) and 3-dose anti-CD4 mAb (anti-CD4x3 group) treated groups showed significantly (p < 0.05) decreased anti-rhGAA antibody levels after 4 weeks of rhGAA treatment when compared to the control group (Fig. 1A). The overall antibody levels for the anti-CD4x3 group remained lower than those of the MTX group throughout the 28-week treatment with rhGAA. Comparing the area under the curve, the anti-CD4x3 group and the MTX group showed a 94.3% and 84.5% reduction of antibody levels, respectively, as compared to the control group (Fig. 1A). Rechallenge with rhGAA at 40 weeks did not significantly change the antibody levels in any of the 3 groups (Fig. 1A). The serum anti-CD4 mAb levels in the anti-CD4x3 group continuously decreased after administration and remained undetectable after 23 weeks (data not shown).

View Article: PubMed Central - PubMed

ABSTRACT

Approximately 35&ndash;40% of patients with classic infantile Pompe disease treated with enzyme replacement therapy (ERT) develop high, sustained antibody titers against the therapeutic enzyme alglucosidase alfa, which abrogates the treatment efficacy. Induction of antigen-specific immune tolerance would greatly enhance ERT for these patients. Here we show that a short-course treatment with non-depleting anti-CD4 monoclonal antibody successfully induced long-term ERT-specific immune tolerance in Pompe disease mice. Our data suggest an effective adjuvant therapy to ERT.

No MeSH data available.