Discovery and multi-parametric optimization of a high-affinity antibody against interleukin-25 with neutralizing activity in a mouse model of skin inflammation

被引：4

作者：

Bone, Ruth ^{[1
]}

Fennell, Brian J. ^{[1
]}

Tam, Amy ^{[2
]}

Sheldon, Richard ^{[3
]}

Nocka, Karl ^{[3
]}

Varghese, Sreeja ^{[1
]}

Chang, Chew Shun ^{[2
]}

Hawerkamp, Heike C. ^{[4
]}

Yeow, Aoife ^{[4
]}

Saunders, Sean P. ^{[4
]}

Hams, Emily ^{[4
]}

Walsh, Patrick T. ^{[5
,6
]}

Cunningham, Orla ^{[7
]}

Fallon, Padraic G. ^{[4
,6
]}

机构：

[1] Pfizer, BioMed Design, Grange Castle Business Pk, Dublin, Ireland

[2] Pfizer, BioMed Design, Cambridge, MA 02139 USA

[3] Pfizer, Inflammat & Immunol, Cambridge, MA 02139 USA

[4] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Med, Dublin, Ireland

[5] Our Ladys Childrens Hosp, Natl Childrens Res Ctr, Dublin, Ireland

[6] St James Hosp, Trinity Translat Med Inst, Trinity Coll Dublin, Dublin, Ireland

[7] UltraHuman Eight Ltd, Sandwich CT13 9FF, Kent, England

来源：

ANTIBODY THERAPEUTICS | 2022年 / 5卷 / 04期

基金：

爱尔兰科学基金会;

关键词：

antibody engineering; interleukin-25; skin inflammation; psoriasis; IL-25; COLITIS;

D O I：

10.1093/abt/tbac022

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Background Interleukin (IL)25 has been implicated in tissue homeostasis at barrier surfaces and the initiation of type two inflammatory signaling in response to infection and cell injury across multiple organs. We sought to discover and engineer a high affinity neutralizing antibody and evaluate the antibody functional activity in vitro and in vivo.Methods In this study, we generated a novel anti-IL25 antibody (22C7) and investigated the antibody's therapeutic potential for targeting IL25 in inflammation.Results A novel anti-IL25 antibody (22C7) was generated with equivalent in vitro affinity and potency against the human and mouse orthologs of the cytokine. This translated into in vivo potency in an IL25-induced air pouch model where 22C7 inhibited the recruitment of monocytes, macrophages, neutrophils and eosinophils. Furthermore, 22C7 significantly reduced ear swelling, acanthosis and disease severity in the Aldara mouse model of psoriasiform skin inflammation. Given the therapeutic potential of IL25 targeting in inflammatory conditions, 22C7 was further engineered to generate a highly developable, fully human antibody while maintaining the affinity and potency of the parental molecule.Conclusions The generation of 22C7, an anti-IL25 antibody with efficacy in a preclinical model of skin inflammation, raises the therapeutic potential for 22C7 use in the spectrum of IL25-mediated diseases. Statement of Significance: We report the generation of a novel mAb, 22C7, against the cytokine interleukin-25. 22C7 inhibited IL25 in vitro and in vivo and suppressed skin inflammation in a mouse model of psoriasis. Antibody engineering strategies humanized and optimized the properties of 22C7 for development for clinical use.

引用

页码：258 / 267

页数：10

共 1 条

[1] Inhibitory Effects Of High-Affinity Ige Receptor (fceri) Binding Antibody Npb311(fab) On Airway Inflammation In An Acute Asthma Mouse Model
Kim, M.
Hong, J.
Bae, J. -H.
Lee, K.
Heo, W.
Kim, M.
Kang, H.
Park, E.
Yoo, K.
Kim, K.
Sohn, M.
Kim, K. -E.
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2014, 189

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