A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity

被引：77

作者：

Karnell, Jodi L. ^{[1
]}

Albulescu, Marius ^{[2
]}

Drabic, Stacey ^{[3
,7
]}

Wang, Liangwei ^{[1
]}

Moate, Rachel ^{[4
]}

Baca, Manuel ^{[3
,7
]}

Oganesyan, Vaheh ^{[3
]}

Gunsior, Michele ^{[1
]}

Thisted, Thomas ^{[3
,8
]}

Yan, Li ^{[1
]}

Li, Jing ^{[5
]}

Xiong, Ximing ^{[3
]}

Eck, Steven C. ^{[3
]}

de los Reyes, Melissa ^{[3
]}

Yusuf, Isharat ^{[3
,9
]}

Streicher, Katie ^{[3
]}

Mueller-Ladner, Ulf ^{[6
]}

Howe, David ^{[4
,10
]}

Ettinger, Rachel ^{[1
]}

Herbst, Ronald ^{[3
]}

Drappa, Jorn ^{[1
]}

机构：

[1] Viela Bio, Gaithersburg, MD 20878 USA

[2] AstraZeneca, Cambridge CB4 0WG, England

[3] MedImmune, Gaithersburg, MD 20878 USA

[4] MedImmune, Granta Pk, Cambridge CB21 6GH, England

[5] MedImmune, San Francisco, CA 94080 USA

[6] Justus Liebig Univ Giessen, Dept Rheumatol & Clin Immunol, Campus Kerchoff, D-61231 Bad Nauheim, Germany

[7] Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA

[8] Antidote Therapeut Inc, Gaithersburg, MD 20878 USA

[9] Gossamer Bio, San Diego, CA 92121 USA

[10] Heptares Therapeut Ltd, Cambridge CB21 6DG, England

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2019年 / 11卷 / 489期

关键词：

ANTI-CD40 LIGAND ANTIBODY; CD40; LIGAND; T-CELLS; B-CELLS; RHEUMATOID-ARTHRITIS; IMMUNE-RESPONSES; EXPRESSION; ANTIGEN; GP39; RECEPTOR;

D O I：

10.1126/scitranslmed.aar6584

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen--specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67(+) dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.

引用

页数：12

共 39 条

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