Depletion of major pathogenic cells in asthma by targeting CRTh2
Tao Huang, Meredith Hazen, Yonglei Shang, Meijuan Zhou, Xiumin Wu, Donghong Yan, Zhonghua Lin, Margaret Solon, Elizabeth Luis, Hai Ngu, Yongchang Shi, Arna Katewa, David F. Choy, Nandhini Ramamoorthi, Erick R. Castellanos, Mercedesz Balazs, Min Xu, Wyne P. Lee, Marissa L. Matsumoto, Jian Payandeh, Joseph R. Arron, Jo-Anne Hongo, Jianyong Wang, Isidro Hötzel, Cary D. Austin, Karin Reif
Tao Huang, Meredith Hazen, Yonglei Shang, Meijuan Zhou, Xiumin Wu, Donghong Yan, Zhonghua Lin, Margaret Solon, Elizabeth Luis, Hai Ngu, Yongchang Shi, Arna Katewa, David F. Choy, Nandhini Ramamoorthi, Erick R. Castellanos, Mercedesz Balazs, Min Xu, Wyne P. Lee, Marissa L. Matsumoto, Jian Payandeh, Joseph R. Arron, Jo-Anne Hongo, Jianyong Wang, Isidro Hötzel, Cary D. Austin, Karin Reif
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Research Article Immunology Therapeutics

Depletion of major pathogenic cells in asthma by targeting CRTh2

Abstract

Eosinophilic inflammation and Th2 cytokine production are central to the pathogenesis of asthma. Agents that target either eosinophils or single Th2 cytokines have shown benefits in subsets of biomarker-positive patients. More broadly effective treatment or disease-modifying effects may be achieved by eliminating more than one inflammatory stimulator. Here we present a strategy to concomitantly deplete Th2 T cells, eosinophils, basophils, and type-2 innate lymphoid cells (ILC2s) by generating monoclonal antibodies with enhanced effector function (19A2) that target CRTh2 present on all 4 cell types. Using human CRTh2 (hCRTh2) transgenic mice that mimic the expression pattern of hCRTh2 on innate immune cells but not Th2 cells, we demonstrate that anti-hCRTh2 antibodies specifically eliminate hCRTh2+ basophils, eosinophils, and ILC2s from lung and lymphoid organs in models of asthma and Nippostrongylus brasiliensis infection. Innate cell depletion was accompanied by a decrease of several Th2 cytokines and chemokines. hCRTh2-specific antibodies were also active on human Th2 cells in vivo in a human Th2-PBMC-SCID mouse model. We developed humanized hCRTh2-specific antibodies that potently induce antibody-dependent cell cytotoxicity (ADCC) of primary human eosinophils and basophils and replicated the in vivo depletion capacity of their murine parent. Therefore, depletion of hCRTh2+ basophils, eosinophils, ILC2, and Th2 cells with h19A2 hCRTh2–specific antibodies may be a novel and more efficacious treatment for asthma.

Authors

Tao Huang, Meredith Hazen, Yonglei Shang, Meijuan Zhou, Xiumin Wu, Donghong Yan, Zhonghua Lin, Margaret Solon, Elizabeth Luis, Hai Ngu, Yongchang Shi, Arna Katewa, David F. Choy, Nandhini Ramamoorthi, Erick R. Castellanos, Mercedesz Balazs, Min Xu, Wyne P. Lee, Marissa L. Matsumoto, Jian Payandeh, Joseph R. Arron, Jo-Anne Hongo, Jianyong Wang, Isidro Hötzel, Cary D. Austin, Karin Reif

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Figure 5

Treatment with anti-hCRTh2 Ab 19A2 eliminates ILC2 cells, eosinophils, and basophils and reduces type-2 inflammatory responses during N. brasiliensis infection.

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Treatment with anti-hCRTh2 Ab 19A2 eliminates ILC2 cells, eosinophils, a...
hCRTh2.BAC.Tg mice were infected with N. brasiliensis 9 days before analysis of tissue and blood samples. Mice were treated with 200 μg of hCRTh2-specific afucosylated Ab 19A2 or control mIgG2a Ab on days –3, 0, 3, and 6. (A–C) Bar graphs show the absolute numbers of eosinophils, basophils, or ILC2 cells as determined by flow cytometry in blood (A), lung (B), or mesenteric LNs (C). (D) Th2 cytokine production was assessed by Luminex in BAL. (E) The dot plot shows the worm burden in the small intestine on day 9 after infection. (F) IgE was assessed by ELISA in serum. (G) Expression levels of chemokine genes were determined by quantitative PCR from RNA isolated from lung on day 9. Values are the relative expression of each gene to the control gene, HPRT. Results are mean ± SEM; number of mice analyzed were for treatment groups (n = 9) and for naive mice (n = 6) except for lung were n = 5 treatment, and n = 3 naive mice were used for cell depletion analyses and the remaining mice (n = 4 and n = 3, respectively) for gene expression studies. *P ≤ 0.05, **P ≤ 0.005, ***P ≤ 0.0005 (Dunnett’s test). LN, lymph node; BAL, bronchoalveolar lavage; HPRT, hypoxanthine guanine phosphoribosyl transferase.