Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes

Yingjuan J. Lu; Leroy W. Wheeler; Haiyan Chu; Paul J. Kleindl; Michael Pugh; Fei You; Satish Rao; Gabriela Garcia; Henry Y. Wu; Andre P. da Cunha; Richard Johnson; Elaine Westrick; Vicky Cross; Alex Lloyd; Christina Dircksen; Patrick J. Klein; Iontcho R. Vlahov; Philip S. Low; Christopher P. Leamon

doi:10.1016/j.xcrm.2021.100422

Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes

Yingjuan J. Lu, Leroy W. Wheeler, Haiyan Chu, Paul J. Kleindl, Michael Pugh, Fei You, Satish Rao, Gabriela Garcia, Henry Y. Wu, Andre P. da Cunha, Richard Johnson, Elaine Westrick, Vicky Cross, Alex Lloyd, Christina Dircksen, Patrick J. Klein, Iontcho R. Vlahov, Philip S. Low, Christopher P. Leamon

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ⁺ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.

Original language	English (US)
Article number	100422
Journal	Cell Reports Medicine
Volume	2
Issue number	10
DOIs	https://doi.org/10.1016/j.xcrm.2021.100422
State	Published - Oct 19 2021

Keywords

adjuvant arthritis
aminopterin
autoimmune uveitis
autoimmunity
cytokine release syndrome
dihydrofolate reductase inhibitor
folate receptor beta
glomerulonephritis
inflammation
monocyte/macrophage activation

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.xcrm.2021.100422

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Lu, Y. J., Wheeler, L. W., Chu, H., Kleindl, P. J., Pugh, M., You, F., Rao, S., Garcia, G., Wu, H. Y., da Cunha, A. P., Johnson, R., Westrick, E., Cross, V., Lloyd, A., Dircksen, C., Klein, P. J., Vlahov, I. R., Low, P. S., & Leamon, C. P. (2021). Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes. Cell Reports Medicine, 2(10), Article 100422. https://doi.org/10.1016/j.xcrm.2021.100422

Lu, YJ, Wheeler, LW, Chu, H, Kleindl, PJ, Pugh, M, You, F, Rao, S, Garcia, G, Wu, HY, da Cunha, AP, Johnson, R, Westrick, E, Cross, V, Lloyd, A, Dircksen, C, Klein, PJ, Vlahov, IR, Low, PS & Leamon, CP 2021, 'Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes', Cell Reports Medicine, vol. 2, no. 10, 100422. https://doi.org/10.1016/j.xcrm.2021.100422

@article{525c48716bf242b3926cab55858ea83b,

title = "Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes",

abstract = "Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ+ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.",

keywords = "adjuvant arthritis, aminopterin, autoimmune uveitis, autoimmunity, cytokine release syndrome, dihydrofolate reductase inhibitor, folate receptor beta, glomerulonephritis, inflammation, monocyte/macrophage activation",

author = "Lu, {Yingjuan J.} and Wheeler, {Leroy W.} and Haiyan Chu and Kleindl, {Paul J.} and Michael Pugh and Fei You and Satish Rao and Gabriela Garcia and Wu, {Henry Y.} and {da Cunha}, {Andre P.} and Richard Johnson and Elaine Westrick and Vicky Cross and Alex Lloyd and Christina Dircksen and Klein, {Patrick J.} and Vlahov, {Iontcho R.} and Low, {Philip S.} and Leamon, {Christopher P.}",

note = "Funding Information: Y.J.L. contributed to activity-based compound design, designed or co-designed in vitro/in vivo studies, and conceptualized/wrote the manuscript. L.W.W. designed/performed flow cytometry and statistical analyses. H.C. designed/performed co-culture experiments. I.R.V. F.Y. and P.J.K. designed/performed chemical synthesis. P.J.K. S.R. and M.P. designed/performed whole-blood stability, linker metabolism, and pharmacokinetic studies. G.G. designed/performed anti-GBM rat experiments. H.Y.W. and A.P.d.C. designed/performed EAU mouse experiments. E.W. V.C. and A.L. performed all in-house animal work. A.L. and C.D. performed cell viability and binding assays. P.S.L. provided general scientific consultation. C.P.L. supervised discovery research and edited/approved the manuscript. I.R.V. C.P.L. F.Y. P.J.K. and Y.J.L. hold a patent in Japan (JP 6772186) for the design and synthesis of EC2319. There is a patent pending in the United States. Publisher Copyright: {\textcopyright} 2021 Novartis Pharmaceuticals",

year = "2021",

month = oct,

day = "19",

doi = "10.1016/j.xcrm.2021.100422",

language = "English (US)",

volume = "2",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "10",

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T1 - Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes

AU - Lu, Yingjuan J.

AU - Wheeler, Leroy W.

AU - Chu, Haiyan

AU - Kleindl, Paul J.

AU - Pugh, Michael

AU - You, Fei

AU - Rao, Satish

AU - Garcia, Gabriela

AU - Wu, Henry Y.

AU - da Cunha, Andre P.

AU - Johnson, Richard

AU - Westrick, Elaine

AU - Cross, Vicky

AU - Lloyd, Alex

AU - Dircksen, Christina

AU - Klein, Patrick J.

AU - Vlahov, Iontcho R.

AU - Low, Philip S.

AU - Leamon, Christopher P.

N1 - Funding Information: Y.J.L. contributed to activity-based compound design, designed or co-designed in vitro/in vivo studies, and conceptualized/wrote the manuscript. L.W.W. designed/performed flow cytometry and statistical analyses. H.C. designed/performed co-culture experiments. I.R.V. F.Y. and P.J.K. designed/performed chemical synthesis. P.J.K. S.R. and M.P. designed/performed whole-blood stability, linker metabolism, and pharmacokinetic studies. G.G. designed/performed anti-GBM rat experiments. H.Y.W. and A.P.d.C. designed/performed EAU mouse experiments. E.W. V.C. and A.L. performed all in-house animal work. A.L. and C.D. performed cell viability and binding assays. P.S.L. provided general scientific consultation. C.P.L. supervised discovery research and edited/approved the manuscript. I.R.V. C.P.L. F.Y. P.J.K. and Y.J.L. hold a patent in Japan (JP 6772186) for the design and synthesis of EC2319. There is a patent pending in the United States. Publisher Copyright: © 2021 Novartis Pharmaceuticals

PY - 2021/10/19

Y1 - 2021/10/19

N2 - Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ+ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.

AB - Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ+ monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development.

KW - adjuvant arthritis

KW - aminopterin

KW - autoimmune uveitis

KW - autoimmunity

KW - cytokine release syndrome

KW - dihydrofolate reductase inhibitor

KW - folate receptor beta

KW - glomerulonephritis

KW - inflammation

KW - monocyte/macrophage activation

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UR - http://www.scopus.com/inward/citedby.url?scp=85119960033&partnerID=8YFLogxK

U2 - 10.1016/j.xcrm.2021.100422

DO - 10.1016/j.xcrm.2021.100422

M3 - Article

C2 - 34755134

AN - SCOPUS:85119960033

SN - 2666-3791

VL - 2

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 10

M1 - 100422

ER -

Targeting folate receptor beta on monocytes/macrophages renders rapid inflammation resolution independent of root causes

Abstract

Keywords

ASJC Scopus subject areas

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