JP-2022533705-A5 -

Dates

Publication Date

20230531

Application Date

20200521

Description

(C. Conclusion) The complement-inhibitory effect of ARGX-117 targeting human C2b was evaluated in an in vitro model using iPSC-derived motor neurons, thereby mimicking the possible pathophysiology of MMN. Data showed that motor neurons in this system expressed complement regulatory proteins, with maximum CD59 expression. Furthermore, it was shown that IgM anti-GM1 antibodies from MMN patients activated the classical complement pathway, and that C3 deposition was dependent on the presence of C2. ARGX-117 efficiently blocked complement activation not only in MMN patients but also in CIDP and GBS patient samples. Additionally, IVIg only blocked complement during the complement activation process and had no effect against anti-idiotype antibodies. This application provides the invention in the following embodiments. (Aspect 1) A method for treating an abnormal proteinogenic neuropathy of a subject, comprising administering a complement system antagonist to the subject, wherein the antagonist inhibits the complement system upstream of complement factor C5. (Aspect 2) The method according to embodiment 1, wherein the antagonist inhibits the classical complement pathway and/or the lectin complement pathway. (Aspect 3) The method according to embodiment 1 or embodiment 2, wherein the abnormal protein neuropathy is demyelinating neuropathy. (Aspect 4) The method according to any one of embodiments 1 to 3, wherein the abnormal proteinogenic neuropathy is characterized by the presence of IgM, IgA, or IgG immunoglobulin. (Aspect 5) The method according to any one of embodiments 1 to 4, wherein the abnormal proteinogenic neuropathy is characterized by the presence of autoantibodies. (Aspect 6) The method according to any one of embodiments 1 to 5, wherein the abnormal proteinogenic neuropathy is characterized by the presence of autoantibodies against neuronal antigens. (Aspect 7) The method according to embodiment 6, wherein the neuronal antigen is a ganglioside or myelin-related glycoprotein (MAG). (Appendix 8) The method according to embodiment 7, wherein the ganglioside is selected from GM1, GM1b, GM2, GM3, GD1a, GD1b, GD2, GD3, GT1a, GT1b, GT3, and GQ1b. (Aspect 9) The method according to embodiment 8, wherein the ganglioside is GM1. (Aspect 10) The method according to any one of embodiments 1 to 9, wherein the abnormal protein neuropathy is selected from: multifocal motor neuropathy (MMN), chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome (GBS), Miller-Fischer syndrome, acute motor axonal neuropathy (AMAN), acute motor sensory axonal neuropathy (AMSAN), chronic ataxic neuropathy-ophthalmopalsy-IgM paraprotein-cold agglutinin-dicialosil antibody (CANOMAD) syndrome, distal acquired demyelinating symmetrical (DADS) neuropathy, monoclonal gammopathy-associated peripheral neuropathy, anti-MAG peripheral neuropathy, and POEMS syndrome. (Phenomenon 11) The method according to embodiment 10, wherein the abnormal proteinogenic neuropathy is MMN, CIDP, or GBS. (Aspect 12) The method according to embodiment 10, wherein the abnormal proteinogenic neuropathy is MMN. (Aspect 13) The method according to any one of embodiments 1 to 12, wherein the antagonist inhibits the complement system upstream of complement factor C3. (Aspect 14) The method according to any one of embodiments 1 to 13, wherein the antagonist inhibits C1, C1q, C1r, or C1s. (Phenomenon 15) The method according to any one of embodiments 1 to 13, wherein the antagonist inhibits complement factors C2, C2a, or C2b. (Aspect 16) The method according to any one of embodiments 1 to 12, wherein the antagonist inhibits complement factors C3, C3a, or C3b. (Aspect 17) The method according to any one of embodiments 1 to 13, wherein the antagonist inhibits complement factors C4, C4a, or C4b. (Phenomenon 18) The method according to any one of embodiments 1 to 17, wherein the antagonist is selected from: inhibitory RNA species, e.g., siRNA or shRNA; small molecule inhibitors; biological antagonists, e.g., inhibitory peptides or antibody mimics, e.g., afibody, affin, afitin, adnectin, atrimer, evasin, DARPin, antikalin, avimer, finomer, versabody, or duocalin; or antibodies or antigen-binding fragments thereof. (Aspect 19) The method according to any one of embodiments 1 to 18, wherein the antagonist is selected from: Compstatin Cp40 (Amyndas); PEG-Cp40 (Amyndas); AMY-101 (Amyndas); AMY-201 (Amyndas); APL-1 and APL-2 (Apellis); Cinryze (Shire); CDX-1135 (Celldex); APT070 mirococept (MRC); HC3-1496 (InCode); Nafamostat (Torii Pharmaceutical); and vaccinia virus complement regulatory protein (VCP). (Aspect 20) The method according to any one of embodiments 1 to 17, wherein the antagonist is an antibody or an antigen-binding fragment thereof. (Aspect 21) The method according to embodiment 20, wherein the antibody is an IgG antibody. (Aspect 22) The method according to embodiment 20, wherein the antigen-binding fragment is selected from: an antibody li