GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis
GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell–mediated diseases, including atopic dermatitis (AD). This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in pat...
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| creator | Guttman-Yassky, Emma Pavel, Ana B. Zhou, Lisa Estrada, Yeriel D. Zhang, Ning Xu, Hui Peng, Xiangyu Wen, Huei-Chi Govas, Panayiota Gudi, Girish CA, Vinu Fang, Hui Salhi, Yacine Back, Jonathan Reddy, Venkateshwar Bissonnette, Robert Maari, Catherine Grossman, Fred Wolff, Gerhard |
| description | GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell–mediated diseases, including atopic dermatitis (AD).
This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD.
Patients with moderate-to-severe AD (affected body surface area, ≥10%; Eczema Area and Severity Index score, ≥12; and inadequate response to topical treatments) were randomized 3:1 to 10 mg/kg intravenous GBR 830 or placebo on day 1 (baseline) and day 29. Biopsy specimens were collected (n = 40) at days 1, 29, and 71. Primary end points included treatment-emergent adverse events (TEAEs) and changes from baseline in biomarkers (epidermal hyperplasia/cytokines) at days 29 and 71.
GBR 830 was well tolerated, with equal TEAE distribution (GBR 830, 63.0% [29/46]; placebo, 63.0% [10/16]). One serious TEAE in the GBR 830 group was deemed unrelated to study drug. At day 71, the proportion of intent-to-treat subjects achieving 50% or greater improvement in Eczema Area and Severity Index score was greater with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant progressive reductions in TH1 (IFN-γ/CXCL10), TH2 (IL-31/CCL11/CCL17), and TH17/TH22 (IL-23p19/IL-8/S100A12) mRNA expression in lesional skin. Significant progressive reductions until day 71 in the drug group were seen in OX40+ T cells and OX40L+ dendritic cells (P |
| doi_str_mv | 10.1016/j.jaci.2018.11.053 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2190107813</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0091674919301915</els_id><sourcerecordid>2268275431</sourcerecordid><originalsourceid>FETCH-LOGICAL-c428t-e6c3afe3524d2310725df912c1ab17ebb71954b735c3c8daf4b94deba8b22a2a3</originalsourceid><addsrcrecordid>eNp9kUFrFTEUhYMo9rX6B1xIwI2LzjQ3mXnJgJtatAqFQlFwFzLJnZrpTOaZZCr9983jVRcuhEC4h-8eknMIeQOsBgbbs7EejfU1Z6BqgJq14hnZAOtktVW8fU42jHVQbWXTHZHjlEZWZqG6l-RIMCkUSNiQu8uPN1QJdkpNKCf76vpHUyY_7-Jyj4mmOx_oLQakyd8Gk9dYRBMctZMP3pqJJrvstYLtTPYYcqK_ff5JTV523lKHcS569ukVeTGYKeHrp_uEfP_86dvFl-rq-vLrxflVZRuucoVbK8yAouWN4wKY5K0bOuAWTA8S-15C1za9FK0VVjkzNH3XOOyN6jk33IgT8v7gW77wa8WU9eyTxWkyAZc1aQ4dK7YKREHf_YOOyxpDeZ3mvKQo20ZAofiBsnFJKeKgd9HPJj5oYHpfhR71vgq9r0ID6FJFWXr7ZL32M7q_K3-yL8CHA4Ali3uPUSdb4rPofESbtVv8__wfAcENmRM</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2268275431</pqid></control><display><type>article</type><title>GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Guttman-Yassky, Emma ; Pavel, Ana B. ; Zhou, Lisa ; Estrada, Yeriel D. ; Zhang, Ning ; Xu, Hui ; Peng, Xiangyu ; Wen, Huei-Chi ; Govas, Panayiota ; Gudi, Girish ; CA, Vinu ; Fang, Hui ; Salhi, Yacine ; Back, Jonathan ; Reddy, Venkateshwar ; Bissonnette, Robert ; Maari, Catherine ; Grossman, Fred ; Wolff, Gerhard</creator><creatorcontrib>Guttman-Yassky, Emma ; Pavel, Ana B. ; Zhou, Lisa ; Estrada, Yeriel D. ; Zhang, Ning ; Xu, Hui ; Peng, Xiangyu ; Wen, Huei-Chi ; Govas, Panayiota ; Gudi, Girish ; CA, Vinu ; Fang, Hui ; Salhi, Yacine ; Back, Jonathan ; Reddy, Venkateshwar ; Bissonnette, Robert ; Maari, Catherine ; Grossman, Fred ; Wolff, Gerhard</creatorcontrib><description>GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell–mediated diseases, including atopic dermatitis (AD).
This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD.
Patients with moderate-to-severe AD (affected body surface area, ≥10%; Eczema Area and Severity Index score, ≥12; and inadequate response to topical treatments) were randomized 3:1 to 10 mg/kg intravenous GBR 830 or placebo on day 1 (baseline) and day 29. Biopsy specimens were collected (n = 40) at days 1, 29, and 71. Primary end points included treatment-emergent adverse events (TEAEs) and changes from baseline in biomarkers (epidermal hyperplasia/cytokines) at days 29 and 71.
GBR 830 was well tolerated, with equal TEAE distribution (GBR 830, 63.0% [29/46]; placebo, 63.0% [10/16]). One serious TEAE in the GBR 830 group was deemed unrelated to study drug. At day 71, the proportion of intent-to-treat subjects achieving 50% or greater improvement in Eczema Area and Severity Index score was greater with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant progressive reductions in TH1 (IFN-γ/CXCL10), TH2 (IL-31/CCL11/CCL17), and TH17/TH22 (IL-23p19/IL-8/S100A12) mRNA expression in lesional skin. Significant progressive reductions until day 71 in the drug group were seen in OX40+ T cells and OX40L+ dendritic cells (P < .001). Hyperplasia measures (thickness/keratin 16/Ki67) showed greater reductions with GBR 830 (P < .001).
Two doses of GBR 830 administered 4 weeks apart were well tolerated and induced significant progressive tissue and clinical changes until day 71 (42 days after the last dose), highlighting the potential of OX40 targeting in patients with AD.
[Display omitted]</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2018.11.053</identifier><identifier>PMID: 30738171</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adult ; Antibodies, Monoclonal, Humanized - administration & dosage ; Antibodies, Monoclonal, Humanized - adverse effects ; Apoptosis ; Atopic dermatitis ; biomarkers ; Biopsy ; CCL17 protein ; costimulation ; CXCL10 protein ; Cytokines ; Cytokines - immunology ; Dendritic cells ; Dermatitis ; Dermatitis, Atopic - drug therapy ; Dermatitis, Atopic - immunology ; Dermatitis, Atopic - pathology ; Eczema ; FDA approval ; Female ; Gene expression ; Gene Expression Regulation - drug effects ; Gene Expression Regulation - immunology ; Helper cells ; Humans ; Hyperplasia ; Hyperplasia - immunology ; Hyperplasia - pathology ; inflammation ; Interleukin 8 ; Intravenous administration ; Keratin ; Lymphocytes ; Lymphocytes T ; Male ; Middle Aged ; Monoclonal antibodies ; OX40 ; Ox40L protein ; Patients ; Population ; Pruritus ; Psoriasis ; Receptors, OX40 - antagonists & inhibitors ; Receptors, OX40 - immunology ; Skin ; Skin - immunology ; Skin - pathology ; Skin diseases ; TH1 ; TH17/TH22 ; TH2 ; Thickness measurement ; trial ; γ-Interferon</subject><ispartof>Journal of allergy and clinical immunology, 2019-08, Vol.144 (2), p.482-493.e7</ispartof><rights>2019 The Authors</rights><rights>Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>2019. The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-e6c3afe3524d2310725df912c1ab17ebb71954b735c3c8daf4b94deba8b22a2a3</citedby><cites>FETCH-LOGICAL-c428t-e6c3afe3524d2310725df912c1ab17ebb71954b735c3c8daf4b94deba8b22a2a3</cites><orcidid>0000-0002-4458-0700</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0091674919301915$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30738171$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guttman-Yassky, Emma</creatorcontrib><creatorcontrib>Pavel, Ana B.</creatorcontrib><creatorcontrib>Zhou, Lisa</creatorcontrib><creatorcontrib>Estrada, Yeriel D.</creatorcontrib><creatorcontrib>Zhang, Ning</creatorcontrib><creatorcontrib>Xu, Hui</creatorcontrib><creatorcontrib>Peng, Xiangyu</creatorcontrib><creatorcontrib>Wen, Huei-Chi</creatorcontrib><creatorcontrib>Govas, Panayiota</creatorcontrib><creatorcontrib>Gudi, Girish</creatorcontrib><creatorcontrib>CA, Vinu</creatorcontrib><creatorcontrib>Fang, Hui</creatorcontrib><creatorcontrib>Salhi, Yacine</creatorcontrib><creatorcontrib>Back, Jonathan</creatorcontrib><creatorcontrib>Reddy, Venkateshwar</creatorcontrib><creatorcontrib>Bissonnette, Robert</creatorcontrib><creatorcontrib>Maari, Catherine</creatorcontrib><creatorcontrib>Grossman, Fred</creatorcontrib><creatorcontrib>Wolff, Gerhard</creatorcontrib><title>GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell–mediated diseases, including atopic dermatitis (AD).
This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD.
Patients with moderate-to-severe AD (affected body surface area, ≥10%; Eczema Area and Severity Index score, ≥12; and inadequate response to topical treatments) were randomized 3:1 to 10 mg/kg intravenous GBR 830 or placebo on day 1 (baseline) and day 29. Biopsy specimens were collected (n = 40) at days 1, 29, and 71. Primary end points included treatment-emergent adverse events (TEAEs) and changes from baseline in biomarkers (epidermal hyperplasia/cytokines) at days 29 and 71.
GBR 830 was well tolerated, with equal TEAE distribution (GBR 830, 63.0% [29/46]; placebo, 63.0% [10/16]). One serious TEAE in the GBR 830 group was deemed unrelated to study drug. At day 71, the proportion of intent-to-treat subjects achieving 50% or greater improvement in Eczema Area and Severity Index score was greater with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant progressive reductions in TH1 (IFN-γ/CXCL10), TH2 (IL-31/CCL11/CCL17), and TH17/TH22 (IL-23p19/IL-8/S100A12) mRNA expression in lesional skin. Significant progressive reductions until day 71 in the drug group were seen in OX40+ T cells and OX40L+ dendritic cells (P < .001). Hyperplasia measures (thickness/keratin 16/Ki67) showed greater reductions with GBR 830 (P < .001).
Two doses of GBR 830 administered 4 weeks apart were well tolerated and induced significant progressive tissue and clinical changes until day 71 (42 days after the last dose), highlighting the potential of OX40 targeting in patients with AD.
[Display omitted]</description><subject>Adult</subject><subject>Antibodies, Monoclonal, Humanized - administration & dosage</subject><subject>Antibodies, Monoclonal, Humanized - adverse effects</subject><subject>Apoptosis</subject><subject>Atopic dermatitis</subject><subject>biomarkers</subject><subject>Biopsy</subject><subject>CCL17 protein</subject><subject>costimulation</subject><subject>CXCL10 protein</subject><subject>Cytokines</subject><subject>Cytokines - immunology</subject><subject>Dendritic cells</subject><subject>Dermatitis</subject><subject>Dermatitis, Atopic - drug therapy</subject><subject>Dermatitis, Atopic - immunology</subject><subject>Dermatitis, Atopic - pathology</subject><subject>Eczema</subject><subject>FDA approval</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene Expression Regulation - immunology</subject><subject>Helper cells</subject><subject>Humans</subject><subject>Hyperplasia</subject><subject>Hyperplasia - immunology</subject><subject>Hyperplasia - pathology</subject><subject>inflammation</subject><subject>Interleukin 8</subject><subject>Intravenous administration</subject><subject>Keratin</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>OX40</subject><subject>Ox40L protein</subject><subject>Patients</subject><subject>Population</subject><subject>Pruritus</subject><subject>Psoriasis</subject><subject>Receptors, OX40 - antagonists & inhibitors</subject><subject>Receptors, OX40 - immunology</subject><subject>Skin</subject><subject>Skin - immunology</subject><subject>Skin - pathology</subject><subject>Skin diseases</subject><subject>TH1</subject><subject>TH17/TH22</subject><subject>TH2</subject><subject>Thickness measurement</subject><subject>trial</subject><subject>γ-Interferon</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUFrFTEUhYMo9rX6B1xIwI2LzjQ3mXnJgJtatAqFQlFwFzLJnZrpTOaZZCr9983jVRcuhEC4h-8eknMIeQOsBgbbs7EejfU1Z6BqgJq14hnZAOtktVW8fU42jHVQbWXTHZHjlEZWZqG6l-RIMCkUSNiQu8uPN1QJdkpNKCf76vpHUyY_7-Jyj4mmOx_oLQakyd8Gk9dYRBMctZMP3pqJJrvstYLtTPYYcqK_ff5JTV523lKHcS569ukVeTGYKeHrp_uEfP_86dvFl-rq-vLrxflVZRuucoVbK8yAouWN4wKY5K0bOuAWTA8S-15C1za9FK0VVjkzNH3XOOyN6jk33IgT8v7gW77wa8WU9eyTxWkyAZc1aQ4dK7YKREHf_YOOyxpDeZ3mvKQo20ZAofiBsnFJKeKgd9HPJj5oYHpfhR71vgq9r0ID6FJFWXr7ZL32M7q_K3-yL8CHA4Ali3uPUSdb4rPofESbtVv8__wfAcENmRM</recordid><startdate>201908</startdate><enddate>201908</enddate><creator>Guttman-Yassky, Emma</creator><creator>Pavel, Ana B.</creator><creator>Zhou, Lisa</creator><creator>Estrada, Yeriel D.</creator><creator>Zhang, Ning</creator><creator>Xu, Hui</creator><creator>Peng, Xiangyu</creator><creator>Wen, Huei-Chi</creator><creator>Govas, Panayiota</creator><creator>Gudi, Girish</creator><creator>CA, Vinu</creator><creator>Fang, Hui</creator><creator>Salhi, Yacine</creator><creator>Back, Jonathan</creator><creator>Reddy, Venkateshwar</creator><creator>Bissonnette, Robert</creator><creator>Maari, Catherine</creator><creator>Grossman, Fred</creator><creator>Wolff, Gerhard</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4458-0700</orcidid></search><sort><creationdate>201908</creationdate><title>GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis</title><author>Guttman-Yassky, Emma ; Pavel, Ana B. ; Zhou, Lisa ; Estrada, Yeriel D. ; Zhang, Ning ; Xu, Hui ; Peng, Xiangyu ; Wen, Huei-Chi ; Govas, Panayiota ; Gudi, Girish ; CA, Vinu ; Fang, Hui ; Salhi, Yacine ; Back, Jonathan ; Reddy, Venkateshwar ; Bissonnette, Robert ; Maari, Catherine ; Grossman, Fred ; Wolff, Gerhard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c428t-e6c3afe3524d2310725df912c1ab17ebb71954b735c3c8daf4b94deba8b22a2a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Antibodies, Monoclonal, Humanized - administration & dosage</topic><topic>Antibodies, Monoclonal, Humanized - adverse effects</topic><topic>Apoptosis</topic><topic>Atopic dermatitis</topic><topic>biomarkers</topic><topic>Biopsy</topic><topic>CCL17 protein</topic><topic>costimulation</topic><topic>CXCL10 protein</topic><topic>Cytokines</topic><topic>Cytokines - immunology</topic><topic>Dendritic cells</topic><topic>Dermatitis</topic><topic>Dermatitis, Atopic - drug therapy</topic><topic>Dermatitis, Atopic - immunology</topic><topic>Dermatitis, Atopic - pathology</topic><topic>Eczema</topic><topic>FDA approval</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Gene Expression Regulation - immunology</topic><topic>Helper cells</topic><topic>Humans</topic><topic>Hyperplasia</topic><topic>Hyperplasia - immunology</topic><topic>Hyperplasia - pathology</topic><topic>inflammation</topic><topic>Interleukin 8</topic><topic>Intravenous administration</topic><topic>Keratin</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Monoclonal antibodies</topic><topic>OX40</topic><topic>Ox40L protein</topic><topic>Patients</topic><topic>Population</topic><topic>Pruritus</topic><topic>Psoriasis</topic><topic>Receptors, OX40 - antagonists & inhibitors</topic><topic>Receptors, OX40 - immunology</topic><topic>Skin</topic><topic>Skin - immunology</topic><topic>Skin - pathology</topic><topic>Skin diseases</topic><topic>TH1</topic><topic>TH17/TH22</topic><topic>TH2</topic><topic>Thickness measurement</topic><topic>trial</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guttman-Yassky, Emma</creatorcontrib><creatorcontrib>Pavel, Ana B.</creatorcontrib><creatorcontrib>Zhou, Lisa</creatorcontrib><creatorcontrib>Estrada, Yeriel D.</creatorcontrib><creatorcontrib>Zhang, Ning</creatorcontrib><creatorcontrib>Xu, Hui</creatorcontrib><creatorcontrib>Peng, Xiangyu</creatorcontrib><creatorcontrib>Wen, Huei-Chi</creatorcontrib><creatorcontrib>Govas, Panayiota</creatorcontrib><creatorcontrib>Gudi, Girish</creatorcontrib><creatorcontrib>CA, Vinu</creatorcontrib><creatorcontrib>Fang, Hui</creatorcontrib><creatorcontrib>Salhi, Yacine</creatorcontrib><creatorcontrib>Back, Jonathan</creatorcontrib><creatorcontrib>Reddy, Venkateshwar</creatorcontrib><creatorcontrib>Bissonnette, Robert</creatorcontrib><creatorcontrib>Maari, Catherine</creatorcontrib><creatorcontrib>Grossman, Fred</creatorcontrib><creatorcontrib>Wolff, Gerhard</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guttman-Yassky, Emma</au><au>Pavel, Ana B.</au><au>Zhou, Lisa</au><au>Estrada, Yeriel D.</au><au>Zhang, Ning</au><au>Xu, Hui</au><au>Peng, Xiangyu</au><au>Wen, Huei-Chi</au><au>Govas, Panayiota</au><au>Gudi, Girish</au><au>CA, Vinu</au><au>Fang, Hui</au><au>Salhi, Yacine</au><au>Back, Jonathan</au><au>Reddy, Venkateshwar</au><au>Bissonnette, Robert</au><au>Maari, Catherine</au><au>Grossman, Fred</au><au>Wolff, Gerhard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2019-08</date><risdate>2019</risdate><volume>144</volume><issue>2</issue><spage>482</spage><epage>493.e7</epage><pages>482-493.e7</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><abstract>GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell–mediated diseases, including atopic dermatitis (AD).
This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD.
Patients with moderate-to-severe AD (affected body surface area, ≥10%; Eczema Area and Severity Index score, ≥12; and inadequate response to topical treatments) were randomized 3:1 to 10 mg/kg intravenous GBR 830 or placebo on day 1 (baseline) and day 29. Biopsy specimens were collected (n = 40) at days 1, 29, and 71. Primary end points included treatment-emergent adverse events (TEAEs) and changes from baseline in biomarkers (epidermal hyperplasia/cytokines) at days 29 and 71.
GBR 830 was well tolerated, with equal TEAE distribution (GBR 830, 63.0% [29/46]; placebo, 63.0% [10/16]). One serious TEAE in the GBR 830 group was deemed unrelated to study drug. At day 71, the proportion of intent-to-treat subjects achieving 50% or greater improvement in Eczema Area and Severity Index score was greater with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant progressive reductions in TH1 (IFN-γ/CXCL10), TH2 (IL-31/CCL11/CCL17), and TH17/TH22 (IL-23p19/IL-8/S100A12) mRNA expression in lesional skin. Significant progressive reductions until day 71 in the drug group were seen in OX40+ T cells and OX40L+ dendritic cells (P < .001). Hyperplasia measures (thickness/keratin 16/Ki67) showed greater reductions with GBR 830 (P < .001).
Two doses of GBR 830 administered 4 weeks apart were well tolerated and induced significant progressive tissue and clinical changes until day 71 (42 days after the last dose), highlighting the potential of OX40 targeting in patients with AD.
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30738171</pmid><doi>10.1016/j.jaci.2018.11.053</doi><orcidid>https://orcid.org/0000-0002-4458-0700</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0091-6749 |
| ispartof | Journal of allergy and clinical immunology, 2019-08, Vol.144 (2), p.482-493.e7 |
| issn | 0091-6749 1097-6825 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2190107813 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Adult Antibodies, Monoclonal, Humanized - administration & dosage Antibodies, Monoclonal, Humanized - adverse effects Apoptosis Atopic dermatitis biomarkers Biopsy CCL17 protein costimulation CXCL10 protein Cytokines Cytokines - immunology Dendritic cells Dermatitis Dermatitis, Atopic - drug therapy Dermatitis, Atopic - immunology Dermatitis, Atopic - pathology Eczema FDA approval Female Gene expression Gene Expression Regulation - drug effects Gene Expression Regulation - immunology Helper cells Humans Hyperplasia Hyperplasia - immunology Hyperplasia - pathology inflammation Interleukin 8 Intravenous administration Keratin Lymphocytes Lymphocytes T Male Middle Aged Monoclonal antibodies OX40 Ox40L protein Patients Population Pruritus Psoriasis Receptors, OX40 - antagonists & inhibitors Receptors, OX40 - immunology Skin Skin - immunology Skin - pathology Skin diseases TH1 TH17/TH22 TH2 Thickness measurement trial γ-Interferon |
| title | GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-04T19%3A01%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=GBR%20830,%20an%20anti-OX40,%20improves%20skin%20gene%20signatures%20and%20clinical%20scores%20in%20patients%20with%20atopic%20dermatitis&rft.jtitle=Journal%20of%20allergy%20and%20clinical%20immunology&rft.au=Guttman-Yassky,%20Emma&rft.date=2019-08&rft.volume=144&rft.issue=2&rft.spage=482&rft.epage=493.e7&rft.pages=482-493.e7&rft.issn=0091-6749&rft.eissn=1097-6825&rft_id=info:doi/10.1016/j.jaci.2018.11.053&rft_dat=%3Cproquest_cross%3E2268275431%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2268275431&rft_id=info:pmid/30738171&rft_els_id=S0091674919301915&rfr_iscdi=true |