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 journalArticlepeer-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 languageEnglish
Pages (from-to)1580-1592
JournalMolecular Therapy
Volume22
Issue number9
Early online date29 Jun 2014
DOIs
Publication statusPublished - 29 Jun 2014

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