Preclinical Safety Profile of a Depleting Antibody against CRTh2 for Asthma: Well Tolerated Despite Unexpected CRTh2 Expression on Vascular Pericytes in the Central Nervous System and Gastric Mucosa
| Autor: | Nga Bien-Ly, Kai H. Barck, Isidro Hötzel, Linda Rangell, Janet Tao, Neeraj Sharma, Arthur Reyes, Kathila S. Rajapaksa, Cary D. Austin, Shannon Liu, Tao Huang, Richard A.D. Carano, Karin Reif, Meire Bremer, Margaret Solon, Sreedevi Chalasani, Angie Yee, Jianyong Wang, Dimitry M. Danilenko, Sarah Paul, Paula Katavolos |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Central Nervous System Endothelium Receptors Prostaglandin Vascular permeability Mice Transgenic Toxicology Blood–brain barrier Risk Assessment Capillary Permeability 03 medical and health sciences 0302 clinical medicine Immune system Gastric mucosa medicine Animals Humans Tissue Distribution Anti-Asthmatic Agents Receptors Immunologic biology business.industry Antibodies Monoclonal Eosinophil Asthma Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Blood-Brain Barrier Gastric Mucosa Immunology Injections Intravenous biology.protein Pericyte Antibody business Pericytes 030215 immunology |
| Zdroj: | Toxicological sciences : an official journal of the Society of Toxicology. 152(1) |
| ISSN: | 1096-0929 |
| Popis: | CRTh2 is expressed on immune cells that drive asthma pathophysiology. Current treatment options for severe asthma are inadequate and therapeutic antibody-mediated depletion of CRTh2-expressing cells represents a promising new therapeutic strategy. Here we report for the first time that CRTh2 is not only expressed on immune cells, but also on microvasculature in the central nervous system (CNS) and gastric mucosa in humans. Microvascular expression of CRTh2 raises a safety concern because a therapeutic antiCRTh2 antibody with enhanced depletion capacity could lead to vascular damage. To evaluate this safety risk, we characterized microvascular expression in human and in transgenic mice expressing human CRTh2 protein (hCRTh2.BAC.Tg) and found that CRTh2 is not localized to microvascular endothelium that is directly exposed to circulating therapeutic antibody, but rather, to pericytes that in the CNS are shielded from direct circulatory exposure by the blood-brain barrier. Immunohistochemical visualization of an intravenously administered antiCRTh2 antibody in transgenic mice revealed localization to microvascular pericytes in the gastric mucosa but not in the CNS, suggesting the blood-brain barrier effectively limits pericyte exposure to circulating therapeutic antibody in the CNS. Repeated dosing with a depleting antiCRTh2 antibody in hCRTh2.BAC.Tg mice revealed linear pharmacokinetics and no drug-related adverse findings in any tissues, including the CNS and gastric mucosa, despite complete depletion of CRTh2 expressing circulating eosinophils and basophils. Collectively, these studies demonstrate that the likelihood of drug-related CNS or gastrointestinal toxicity in humans treated with a therapeutic depleting antiCRTh2 antibody is low despite pericyte expression of CRTh2 in these tissues. |
| Databáze: | OpenAIRE |
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