Characterisation of a novel Fc conjugate of Macrophage Colony-Stimulating Factor (CSF1)

Deborah Gow; Kristin A Sauter; Clare Pridans; Lindsey Moffat; Anuj Sehgal; Ben M Stutchfield; Sobia Raza; Philippa M Beard; Yi Ting Tsai; Graeme Bainbridge; Pamela L Boner; Greg Fici; David Garcia-Tapia; Roger A Martin; Theodore Oliphant; John A Shelly; Raksha Tiwari; Thomas L Wilson; Lee B Smith; Neil A Mabbott; David A Hume

doi:10.1038/mt.2014.112

Characterisation of a novel Fc conjugate of Macrophage Colony-Stimulating Factor (CSF1)

Deborah Gow, Kristin A Sauter, Clare Pridans, Lindsey Moffat, Anuj Sehgal, Ben M Stutchfield, Sobia Raza, Philippa M Beard, Yi Ting Tsai, Graeme Bainbridge, Pamela L Boner, Greg Fici, David Garcia-Tapia, Roger A Martin, Theodore Oliphant, John A Shelly, Raksha Tiwari, Thomas L Wilson, Lee B Smith, Neil A MabbottDavid A Hume

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

Abstract

We have produced an Fc conjugate of CSF1 with an improved circulating half-life. CSF1-Fc retained its macrophage growth-promoting activity, and did not induce proinflammatory cytokines in-vitro. Treatment with CSF1-Fc did not produce adverse effects in mice or pigs. The impact of CSF1-Fc was examined using the Csf1r-EGFP reporter gene in MacGreen mice. Administration of CSF1-Fc to mice drove extensive infiltration of all tissues by Csf1r-EGFP positive macrophages. The main consequence was hepatosplenomegaly, associated with proliferation of hepatocytes. Expression profiles of the liver indicated that infiltrating macrophages produced candidate mediators of hepatocyte proliferation including urokinase, TNF and IL6. CSF1-Fc also promoted osteoclastogenesis and produced pleiotropic effects on other organ systems, notably the testis, where CSF1-dependent macrophages have been implicated in homeostasis. However, it did not affect other putative CSF1 targets, notably intestine, where Paneth cell numbers and villus architecture were unchanged. CSF1 has therapeutic potential in regenerative medicine in multiple organs. We suggest that the CSF1-Fc conjugate retains this potential, and may permit daily delivery by injection rather than continuous infusion required for the core molecule.Molecular Therapy (2014); doi:10.1038/mt.2014.112.

Original language	English
Pages (from-to)	1580-1592
Journal	Molecular Therapy
Volume	22
Issue number	9
Early online date	29 Jun 2014
DOIs	https://doi.org/10.1038/mt.2014.112
Publication status	Published - 29 Jun 2014

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10.1038/mt.2014.112

Characterisation of a novel Fc conjugate of Macrophage Colony-Stimulating Factor (CSF1)
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http://www.nature.com/mt/journal/vaop/naam/abs/mt2014112a.html

Eastbio Doctoral Training Partnership
Farquharson, C. (Principal Investigator) & MacRae, V. (Co-investigator)
BBSRC
1/10/12 → 30/09/18
Project: Research
Innate immunity and endemic diseases in livestock species
Collie, D. (Principal Investigator), Beard, P. (Co-investigator), Bishop, S. (Co-investigator), Bronsvoort, M. (Co-investigator), Burt, D. (Co-investigator), Fitzgerald, R. (Co-investigator), Freeman, T. (Co-investigator), Gally, D. (Co-investigator), Gill, A. (Co-investigator), Glass, E. (Co-investigator), Hocking, P. (Co-investigator), Hope, J. (Co-investigator), Hume, D. (Co-investigator), Kaiser, P. (Co-investigator), Mabbott, N. (Co-investigator), McLachlan, G. (Co-investigator), Morrison, L. (Co-investigator), Stevens, J. (Co-investigator), Stevens, M. (Co-investigator) & Watson, M. (Co-investigator)
BBSRC
1/04/12 → 31/03/17
Project: Research
Development of applications of CSF-1 and IL34 in livestock
Hume, D. (Principal Investigator), Gill, A. (Co-investigator) & Sang, H. (Co-investigator)
BBSRC
16/01/12 → 31/03/15
Project: Research

Clare Pridans
- Deanery of Clinical Sciences - Research Fellow
- Centre for Inflammation Research
Person: Academic: Research Active

Cite this

Gow, D., Sauter, K. A., Pridans, C., Moffat, L., Sehgal, A., Stutchfield, B. M., Raza, S., Beard, P. M., Tsai, Y. T., Bainbridge, G., Boner, P. L., Fici, G., Garcia-Tapia, D., Martin, R. A., Oliphant, T., Shelly, J. A., Tiwari, R., Wilson, T. L., Smith, L. B., ... Hume, D. A. (2014). Characterisation of a novel Fc conjugate of Macrophage Colony-Stimulating Factor (CSF1). Molecular Therapy, 22(9), 1580-1592. https://doi.org/10.1038/mt.2014.112

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title = "Characterisation of a novel Fc conjugate of Macrophage Colony-Stimulating Factor (CSF1)",

abstract = "We have produced an Fc conjugate of CSF1 with an improved circulating half-life. CSF1-Fc retained its macrophage growth-promoting activity, and did not induce proinflammatory cytokines in-vitro. Treatment with CSF1-Fc did not produce adverse effects in mice or pigs. The impact of CSF1-Fc was examined using the Csf1r-EGFP reporter gene in MacGreen mice. Administration of CSF1-Fc to mice drove extensive infiltration of all tissues by Csf1r-EGFP positive macrophages. The main consequence was hepatosplenomegaly, associated with proliferation of hepatocytes. Expression profiles of the liver indicated that infiltrating macrophages produced candidate mediators of hepatocyte proliferation including urokinase, TNF and IL6. CSF1-Fc also promoted osteoclastogenesis and produced pleiotropic effects on other organ systems, notably the testis, where CSF1-dependent macrophages have been implicated in homeostasis. However, it did not affect other putative CSF1 targets, notably intestine, where Paneth cell numbers and villus architecture were unchanged. CSF1 has therapeutic potential in regenerative medicine in multiple organs. We suggest that the CSF1-Fc conjugate retains this potential, and may permit daily delivery by injection rather than continuous infusion required for the core molecule.Molecular Therapy (2014); doi:10.1038/mt.2014.112.",

author = "Deborah Gow and Sauter, {Kristin A} and Clare Pridans and Lindsey Moffat and Anuj Sehgal and Stutchfield, {Ben M} and Sobia Raza and Beard, {Philippa M} and Tsai, {Yi Ting} and Graeme Bainbridge and Boner, {Pamela L} and Greg Fici and David Garcia-Tapia and Martin, {Roger A} and Theodore Oliphant and Shelly, {John A} and Raksha Tiwari and Wilson, {Thomas L} and Smith, {Lee B} and Mabbott, {Neil A} and Hume, {David A}",

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Gow, D, Sauter, KA, Pridans, C , Moffat, L, Sehgal, A, Stutchfield, BM, Raza, S, Beard, PM, Tsai, YT, Bainbridge, G, Boner, PL, Fici, G, Garcia-Tapia, D, Martin, RA, Oliphant, T, Shelly, JA, Tiwari, R, Wilson, TL, Smith, LB, Mabbott, NA & Hume, DA 2014, 'Characterisation of a novel Fc conjugate of Macrophage Colony-Stimulating Factor (CSF1)', Molecular Therapy, vol. 22, no. 9, pp. 1580-1592. https://doi.org/10.1038/mt.2014.112

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T1 - Characterisation of a novel Fc conjugate of Macrophage Colony-Stimulating Factor (CSF1)

AU - Gow, Deborah

AU - Sauter, Kristin A

AU - Pridans, Clare

AU - Moffat, Lindsey

AU - Sehgal, Anuj

AU - Stutchfield, Ben M

AU - Raza, Sobia

AU - Beard, Philippa M

AU - Tsai, Yi Ting

AU - Bainbridge, Graeme

AU - Boner, Pamela L

AU - Fici, Greg

AU - Garcia-Tapia, David

AU - Martin, Roger A

AU - Oliphant, Theodore

AU - Shelly, John A

AU - Tiwari, Raksha

AU - Wilson, Thomas L

AU - Smith, Lee B

AU - Mabbott, Neil A

AU - Hume, David A

PY - 2014/6/29

Y1 - 2014/6/29

N2 - We have produced an Fc conjugate of CSF1 with an improved circulating half-life. CSF1-Fc retained its macrophage growth-promoting activity, and did not induce proinflammatory cytokines in-vitro. Treatment with CSF1-Fc did not produce adverse effects in mice or pigs. The impact of CSF1-Fc was examined using the Csf1r-EGFP reporter gene in MacGreen mice. Administration of CSF1-Fc to mice drove extensive infiltration of all tissues by Csf1r-EGFP positive macrophages. The main consequence was hepatosplenomegaly, associated with proliferation of hepatocytes. Expression profiles of the liver indicated that infiltrating macrophages produced candidate mediators of hepatocyte proliferation including urokinase, TNF and IL6. CSF1-Fc also promoted osteoclastogenesis and produced pleiotropic effects on other organ systems, notably the testis, where CSF1-dependent macrophages have been implicated in homeostasis. However, it did not affect other putative CSF1 targets, notably intestine, where Paneth cell numbers and villus architecture were unchanged. CSF1 has therapeutic potential in regenerative medicine in multiple organs. We suggest that the CSF1-Fc conjugate retains this potential, and may permit daily delivery by injection rather than continuous infusion required for the core molecule.Molecular Therapy (2014); doi:10.1038/mt.2014.112.

AB - We have produced an Fc conjugate of CSF1 with an improved circulating half-life. CSF1-Fc retained its macrophage growth-promoting activity, and did not induce proinflammatory cytokines in-vitro. Treatment with CSF1-Fc did not produce adverse effects in mice or pigs. The impact of CSF1-Fc was examined using the Csf1r-EGFP reporter gene in MacGreen mice. Administration of CSF1-Fc to mice drove extensive infiltration of all tissues by Csf1r-EGFP positive macrophages. The main consequence was hepatosplenomegaly, associated with proliferation of hepatocytes. Expression profiles of the liver indicated that infiltrating macrophages produced candidate mediators of hepatocyte proliferation including urokinase, TNF and IL6. CSF1-Fc also promoted osteoclastogenesis and produced pleiotropic effects on other organ systems, notably the testis, where CSF1-dependent macrophages have been implicated in homeostasis. However, it did not affect other putative CSF1 targets, notably intestine, where Paneth cell numbers and villus architecture were unchanged. CSF1 has therapeutic potential in regenerative medicine in multiple organs. We suggest that the CSF1-Fc conjugate retains this potential, and may permit daily delivery by injection rather than continuous infusion required for the core molecule.Molecular Therapy (2014); doi:10.1038/mt.2014.112.

U2 - 10.1038/mt.2014.112

DO - 10.1038/mt.2014.112

M3 - Article

C2 - 24962162

SN - 1525-0016

VL - 22

SP - 1580

EP - 1592

JO - Molecular Therapy

JF - Molecular Therapy

IS - 9

ER -

Characterisation of a novel Fc conjugate of Macrophage Colony-Stimulating Factor (CSF1)

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Projects

Eastbio Doctoral Training Partnership

Innate immunity and endemic diseases in livestock species

Development of applications of CSF-1 and IL34 in livestock

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Clare Pridans

Cite this