Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection

被引：30

作者：

VanDyke, Derek ^{[1
,2
]}

Iglesias, Marcos ^{[3
]}

Tomala, Jakub ^{[4
]}

Young, Arabella ^{[5
,6
,7
,8
]}

Smith, Jennifer ^{[5
]}

Perry, Joseph A. ^{[9
]}

Gebara, Edward ^{[2
,10
]}

Cross, Amy R. ^{[11
]}

Cheung, Laurene S. ^{[12
,13
]}

Dykema, Arbor G. ^{[12
,13
]}

Orcutt-Jahns, Brian T. ^{[14
]}

Henclova, Tereza ^{[4
]}

Golias, Jaroslav ^{[15
]}

Balolong, Jared ^{[5
]}

Tomasovic, Luke M. ^{[1
,2
]}

Funda, David ^{[15
]}

Meyer, Aaron S. ^{[14
]}

Pardoll, Drew M. ^{[12
,13
]}

Hester, Joanna ^{[11
]}

Issa, Fadi ^{[11
]}

Hunter, Christopher A. ^{[9
]}

Anderson, Mark S. ^{[5
]}

Bluestone, Jeffrey A. ^{[5
,6
,16
]}

Raimondi, Giorgio ^{[3
]}

Spangler, Jamie B. ^{[1
,2
,12
,13
,17
,18
,19
]}

机构：

[1] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA

[2] Johns Hopkins Univ, Sch Med, Translat Tissue Engn Ctr, Baltimore, MD 21231 USA

[3] Johns Hopkins Univ, Sch Med, Dept Plast & Reconstruct Surg, Vascularized Composite Allotransplantat Lab, Baltimore, MD 21205 USA

[4] Acad Sci Czech Republ, Inst Biotechnol, Vestec 25250, Czech Republic

[5] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA

[6] Univ Calif San Francisco, Sean N Parker Autoimmune Res Lab, San Francisco, CA 94143 USA

[7] Univ Utah, Huntsman Canc Inst, Hlth Sci Ctr, Salt Lake City, UT 84112 USA

[8] Univ Utah, Sch Med, Dept Pathol, Salt Lake City, UT 84112 USA

[9] Univ Penn, Dept Pathobiol, Philadelphia, PA 19104 USA

[10] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA

[11] Univ Oxford, Nuffield Dept Surg Sci, Translat Res Immunol Grp, Oxford OX3 9DU, England

[12] Johns Hopkins Univ, Bloomberg Kimmel Inst Canc Immunotherapy, Baltimore, MD 21231 USA

[13] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

[14] Univ Calif Los Angeles, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell, Jonsson Comprehens Canc Ctr, Dept Bioengn, Los Angeles, CA 90095 USA

[15] Acad Sci Czech Republ, Inst Microbiol, Prague 14220, Czech Republic

[16] Sonoma Biotherapeut, San Francisco, CA 94080 USA

[17] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA

[18] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA

[19] Johns Hopkins Univ, Sch Med, Dept Ophthalmol, Baltimore, MD 21287 USA

来源：

CELL REPORTS | 2022年 / 41卷 / 03期

基金：

英国惠康基金;

关键词：

IN-VIVO EXPANSION; IL-2; RECEPTOR; MONOCLONAL-ANTIBODY; INDUCED COLITIS; INTERLEUKIN-2; CYTOKINE; COMPLEXES; SUPERAGONIST; INDUCTION; BINDING;

D O I：

10.1016/j.celrep.2022.111478

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

引用

页数：31

共 102 条

[51] Anti-cancer Therapies Employing IL-2 Cytokine Tumor Targeting: Contribution of Innate, Adaptive and Immunosuppressive Cells in the Anti-tumor Efficacy [J].

Mortara, Lorenzo ;

Balza, Enrica ;

Bruno, Antonino ;

Poggi, Alessandro ;

Orecchia, Paola ;

Carnemolla, Barbara .

FRONTIERS IN IMMUNOLOGY, 2018, 9

[52] The JAK-STAT signaling pathway: Input and output intergration [J].

Murray, Peter J. .

JOURNAL OF IMMUNOLOGY, 2007, 178 (05) :2623-2629

[53] A NOVEL METHOD IN THE INDUCTION OF RELIABLE EXPERIMENTAL ACUTE AND CHRONIC ULCERATIVE-COLITIS IN MICE [J].

OKAYASU, I ;

HATAKEYAMA, S ;

YAMADA, M ;

OHKUSA, T ;

INAGAKI, Y ;

NAKAYA, R .

GASTROENTEROLOGY, 1990, 98 (03) :694-702

[54] Decrease of Foxp3+ Treg Cell Number and Acquisition of Effector Cell Phenotype during Lethal Infection [J].

Oldenhove, Guillaume ;

Bouladoux, Nicolas ;

Wohlfert, Elizabeth A. ;

Hall, Jason A. ;

Chou, David ;

Dos Santos, Liliane ;

O'Brien, Shaun ;

Blank, Rebecca ;

Lamb, Erika ;

Natarajan, Sundar ;

Kastenmayer, Robin ;

Hunter, Christopher ;

Grigg, Michael E. ;

Belkaid, Yasmine .

IMMUNITY, 2009, 31 (05) :772-786

[55]

Ongaro Tiziano, 2020, Oncotarget, V11, P3698, DOI 10.18632/oncotarget.27726

[56]

Pedregosa F, 2011, J MACH LEARN RES, V12, P2825

[57] A long-lived IL-2 mutein that selectively activates and expands regulatory T cells as a therapy for autoimmune disease [J].

Peterson, Laurence B. ;

Bell, Charles J. M. ;

Howlett, Sarah K. ;

Pekalski, Marcin L. ;

Brady, Kevin ;

Hinton, Heather ;

Sauter, Denise ;

Todd, John A. ;

Umana, Pablo ;

Ast, Oliver ;

Waldhauer, Inja ;

Freimoser-Grundschober, Anne ;

Moessner, Ekkehard ;

Klein, Christian ;

Hosse, Ralf J. ;

Wicker, Linda S. .

JOURNAL OF AUTOIMMUNITY, 2018, 95 :1-14

[58] Autoimmune Endocrinopathies: An Emerging Complication of Immune Checkpoint Inhibitors [J].

Quandt, Zoe ;

Young, Arabella ;

Perdigoto, Ana Luisa ;

Herold, Kevan C. ;

Anderson, Mark S. .

ANNUAL REVIEW OF MEDICINE, VOL 72, 2021, 2021, 72 :313-330

[59] First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation [J].

Romee, Rizwan ;

Cooley, Sarah ;

Berrien-Elliott, Melissa M. ;

Westervelt, Peter ;

Verneris, Michael R. ;

Wagner, John E. ;

Weisdorf, Daniel J. ;

Blazar, Bruce R. ;

Ustun, Celalettin ;

Defor, Todd E. ;

Vivek, Sithara ;

Peck, Lindsey ;

DiPersio, John F. ;

Cashen, Amanda F. ;

Kyllo, Rachel ;

Musiek, Amy ;

Schaffer, Andras ;

Anadkat, Milan J. ;

Rosman, Ilana ;

Miller, Daniel ;

Egan, Jack O. ;

Jeng, Emily K. ;

Rock, Amy ;

Wong, Hing C. ;

Fehniger, Todd A. ;

Miller, Jeffrey S. .

BLOOD, 2018, 131 (23) :2515-2527

[60]

Rondon I.J., 2015, Anti -IL -2 Antibodies and Compositions and Uses Thereof

← 1 2 3 4 5 6 7 8 9 10 →