Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcγRIIb with Fc-engineered antibody Seung Y. Chu, PhD, Holly M. Horton, PhD,

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Presentation transcript:

Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcγRIIb with Fc-engineered antibody Seung Y. Chu, PhD, Holly M. Horton, PhD, Erik Pong, MS, Irene W.L. Leung, PhD, Hsing Chen, MS, Duc-Hanh Nguyen, BS, Cristina Bautista, BS, Umesh S. Muchhal, PhD, Matthew J. Bernett, PhD, Gregory L. Moore, PhD, David E. Szymkowski, PhD, John R. Desjarlais, PhD Journal of Allergy and Clinical Immunology Volume 129, Issue 4, Pages 1102-1115 (April 2012) DOI: 10.1016/j.jaci.2011.11.029 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Increased affinity for soluble human IgE and FcγRIIb of XmAb7195 relative to omalizumab. Surface plasmon resonance traces of Fv domain of full-length antibody binding to IgE (left panel) and of Fc domain of full-length antibody binding to Fc inhibitory receptor FcγRIIb (right panel). See Table I for affinity determinations. Binding curves for IgE were performed at 3.13, 6.25, 12.5, and 25.0 nM; binding curves for FcγRIIb were performed at 15.62, 62.5, 250, and 1000 nM. Journal of Allergy and Clinical Immunology 2012 129, 1102-1115DOI: (10.1016/j.jaci.2011.11.029) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Inhibition of IgE but not IgG2 or IgM production by XmAb7195 in cultured human PBMCs. PBMCs were cultured for 14 days to stimulate the differentiation of B cells into plasma cells and subsequent production of immunoglobulins. Results shown represent 1 study of PBMCs from a single healthy donor and are representative of at least 4 independent experiments using PBMCs from 4 donors. Dose responses were fit by using linear regression of log-transformed data, and slopes and standard errors were calculated for each group. A 1-way ANOVA with Dunnett posttest for multiple comparisons was then used to compare all groups versus isotype control XENP6003. The suppressive effect of XmAb7195 is significant for IgE but not for IgM or IgG2 (***P < .001); if unlabeled, not significant (P > .05). Journal of Allergy and Clinical Immunology 2012 129, 1102-1115DOI: (10.1016/j.jaci.2011.11.029) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Suppression of human IgE but not IgG production by XmAb7195 in huSCID mice. PBMCs were engrafted on day 0, antibodies (10 mg/kg) were given on days 9 and 24, and total human IgE and IgG levels were measured in mouse serum at days 8, 23, and 36. A, Total serum IgE levels. B, Total serum IgG levels. C and D, Data for A and B, respectively, plotted as the time course of group averages. Results are representative of at least 4 similar experiments. Data are for 8 mice per group, and error bars represent mean ± SEM of log-transformed values. P values in all panels represent 1-way ANOVA with Dunnett posttest for multiple comparisons (vs vehicle at same time point); **P < .01; if unlabeled, not significant (P > .05). Values below assay limit of quantitation in A (32 ng/mL) are plotted at this baseline. Journal of Allergy and Clinical Immunology 2012 129, 1102-1115DOI: (10.1016/j.jaci.2011.11.029) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Suppression of free and total human IgE levels by XmAb7195 in huSCID model. PBMCs were engrafted on day 0, blood was drawn on day 7 to determine baselines, antibodies (10 mg/kg) were given once on day 8, and free and total human IgE levels in mouse serum were measured at times shown (day 8 blood was drawn 1 h after antibody injection). A, Free IgE levels. B, Total IgE levels. C, Drug levels in serum. Data are for 8 mice per group, and error bars represent mean ± SEM of log-transformed values. P values in A and B represent repeated-measures 1-way ANOVA with Dunnett posttest for multiple comparisons (vs vehicle); ***P < .001; *P < .05; if unlabeled, not significant (P > .05). Values below assay limits of quantitation in A and B (2 and 26 ng/mL, respectively) are plotted at these baselines. Journal of Allergy and Clinical Immunology 2012 129, 1102-1115DOI: (10.1016/j.jaci.2011.11.029) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Suppression of IgE in established huSCID model with high baseline IgE levels. Antibodies were dosed twice weekly for 14 days starting immediately after blood was drawn on day 21. A, Free human IgE levels. B, Total human IgE levels. C, Total human IgG2 levels. D, Drug levels in day 35 serum. Data are for 10 mice per group, and error bars represent mean ± SEM of log-transformed values. P values in A, B, and C represent 1-way ANOVA with Dunnett posttest for multiple comparisons (vs vehicle at the same time point); *P < .05; ***P < .001; if unlabeled, not significant (P > .05). Values below assay limit of quantitation in A and B (2.6 ng/mL) are plotted at this baseline. Journal of Allergy and Clinical Immunology 2012 129, 1102-1115DOI: (10.1016/j.jaci.2011.11.029) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Selective and nonselective reduction of human IgE, IgG, and IgM in huSCID model. Mice received a single 10 mg/kg dose of antibodies 8 days after engraftment with human PBMCs, and serum was collected 14 days later. Data are for 8 mice per group, and error bars represent mean ± SEM of log-transformed values. P values represent 1-way ANOVA with Dunnett posttest for multiple comparisons (vs vehicle for the same isotype); **P < .01; *P < .05; if unlabeled, not significant (P > .05). Data for vehicle and XmAb5871 controls have been previously reported.19 Journal of Allergy and Clinical Immunology 2012 129, 1102-1115DOI: (10.1016/j.jaci.2011.11.029) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Efficacy of mouse anti-IgE surrogates in C57BL/6 mice transgenic for human FcγRIIb. XENP8252 and XENP8253 are surrogates for omalizumab and XmAb7195, respectively. Mice were treated with vehicle or 10 mg/kg antibodies twice weekly starting on day 0. A, Free mouse IgE levels. B, Total mouse IgE levels. C, Total mouse IgG levels. Data are for 10 mice per group, and error bars represent mean ± SEM of log-transformed values. Results are representative of 2 similar experiments. P values represent repeated-measures 1-way ANOVA with Dunnett posttest for multiple comparisons (vs vehicle); ***P < .001; **P < .01; *P < .05; if unlabeled, not significant (P > .05). Values below assay limits of quantitation in A and B (15.6 and 2.6 ng/mL, respectively) are plotted at these baselines. Journal of Allergy and Clinical Immunology 2012 129, 1102-1115DOI: (10.1016/j.jaci.2011.11.029) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 IgE+ B-cell activation by polyclonal anti-IgE antibody and its suppression by XmAb7195 in huSCID mice. A, Increasing concentrations of polyclonal anti-IgE activate human B cells and stimulate human IgE production (measured 20 days after engraftment and 11 days after anti-IgE treatment). XmAb7195 (10 mg/kg) suppresses IgE production under all anti-IgE treatment conditions. B, Increase in total IgE levels induced by polyclonal anti-IgE is suppressed by XmAb7195 but not by FcγR knockout control XENP7196. P values in A represent Student t tests versus vehicle at the same time point and in B represent 1-way ANOVA with Dunnett posttest for multiple comparisons versus vehicle; **P < .01; ***P < .001; **** P < .0001; if unlabeled, not significant (P > .05). Values below assay limits of quantitation in A and B (20 and 98 ng/mL, respectively) are plotted at these baselines. Journal of Allergy and Clinical Immunology 2012 129, 1102-1115DOI: (10.1016/j.jaci.2011.11.029) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions