Methods of treating paraproteinemic neuropathy with anti-C2 antibodies
The present invention relates to a method of treating a paraproteinemic neuropathy in a subject by administering to the subject an antagonist of the complement system. The antagonist inhibits the complement system upstream of complement factor C5. More specifically, the antagonist may be an antibody or an antigen-binding fragment thereof that blocks or inhibits the complement system by inhibiting the C2b domain of complement factor C2. The paraproteinemic neuropathies that may be treated include, in particular, multifocal motor neuropathy (MMN), chronic inflammatory demyelinating polyneuropathy (CIDP), and Guillain-Barre syndrome (GBS).
1 . A method of treating a paraproteinemic neuropathy in a subject, the method comprising administering to the subject an anti-C2 antibody or antigen-binding fragment thereof comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 8, and the VL comprises complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 7, 6, and 5, respectively.
2 . The method of claim 1 , wherein the anti-C2 antibody or antigen-binding fragment thereof inhibits the classical complement pathway and/or the lectin complement pathway.
3 . The method of claim 1 , wherein the paraproteinemic neuropathy is a demyelinating neuropathy.
4 . The method of claim 1 , wherein the paraproteinemic neuropathy is characterised by the presence of autoantibodies, optionally wherein the autoantibodies target a neural antigen.
5 . The method of claim 4 , wherein the neural antigen is a ganglioside or myelin-associated glycoprotein (MAG), optionally wherein the ganglioside is selected from the group consisting of GM1, GM1b, GM2, GM3, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GT3, and GQ1b.
6 . The method of claim 1 , wherein the paraproteinemic neuropathy is selected from the group consisting of: multifocal motor neuropathy (MMN), chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barre syndrome (GBS), Miller Fisher syndrome, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), chronic ataxic neuropathy-ophthalmoplegia-IgM paraprotein-cold agglutinins-disialosyl antibodies (CANOMAD) syndrome, distal acquired demyelinating symmetric (DADS) neuropathy, monoclonal gammopathy associated peripheral neuropathy, anti-MAG peripheral neuropathy, and POEMS syndrome.
7 . The method of claim 1 , wherein the VL comprises the amino acid sequence of SEQ ID NO: 9.
8 . The method of claim 1 , wherein the antibody or antigen-binding fragment comprises a human IgG heavy chain constant domain.
9 . The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 16 and a light chain comprising the amino acid sequence of SEQ ID NO: 20.
10 . The method of claim 1 , further comprising administering intravenous immunoglobulin to the subject.
11 . The method of claim 1 , further comprising administering rituximab to the subject.