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Presentation transcript:

Moss-made Biopharmaceuticals Moss-FH 03/2018

Moss-FH Complement Factor H for aHUS 3/21/2018

Complement factor H Structure [1] Function [1] Approx. 150 kDa Numerous aa-sequence polymorphisms described 20 repetitive domains (SCR) 40 di-sulfide bonds 8 N-Glycosylation sites Function [1] Central regulator in alternative pathway of complement system Mutations in FH lead to: Functional impairment Unregulated complement activation atypical HUS (chronic risk of complement-mediated thrombotic microangiopathy (TMA)) [1]: Merle et al, Front Immunol. 2015 Jun 2;6:262. 3/21/2018

Complement System Factor H – a central complement regulator [1,2] Factor H is the major fluid-phase regulator of the alternative pathway, as it prevents the formation of the C3 and C5 convertases, facilitates the disassembly of already formed convertases and acts as a cofactor for the inactivation (enzymatic cleavage) of C3b. Source: Kopp et al, 2012 [1]: Merle et al, Front Immunol. 2015 Jun 2;6:262; [2]: Kopp et al, Biomolecules 2012, 2(1), 46-75 3/21/2018

Complement Factor H Glomerulonephritis Central complement regulator FH-mutations lead to: C3 Glomerulopathy (C3G) Membranoproliferative Glomerulonephritis due to C3 depositions in glomeroli atypical HUS (aHUS) chronic risk of complement dependant thrombotic microangiopathy (TMA) Glomerulonephritis due to C3 depositions Glomerulonephritis Source: http://pnhahus.com.au TMA 3/21/2018

Market atypical haemolytic uremic syndrome (aHUS) C3G no approved therapeutic product aHUS Unregulated complement activation ~30% caused by mutations in human CFH gene Atypical HUS (chronic risk of complement- mediated thrombotic microangiopathy (TMA)) Approved medical treatment Soliris (Alexion) monoclonal antibody (mAb) binds to C5 Blocks formation of terminal MAC (membrane attack complex) Approved for: Paroxysomal nocturnal haemoglobinurea (PNH) Atypical haemolytic uraemic syndrome (aHUS) Source: Alexion Pharmaceuticals 2015 Annual Report 3/21/2018

In vitro activity of moss-FH Soliris Moss-FH: Promotes cleavage of C3b α-chain Degrades C3-convertase Reduces formation of membrane attack complex 3/21/2018 Sd-FH: human serum derived FH

Immunofluorescence stain, kidney, C3–Alexa488, 63x In vivo activity Increase of serum C3 levels (assayed with C3-ELISA) Reduction of adverse C3 deposits in mice kidney (Immunostaining) Immunofluorescence stain, kidney, C3–Alexa488, 63x Study setup: double i.v.-injection 2h apart, 0.5mg FH each, moss-FH (n=5), Controls (n=5; human serum derived (sd) FH and PBS) 3/21/2018

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