ARGX-117, a therapeutic complement inhibiting antibody targeting C2

Abstract

Background Activation of the classical and lectin pathway of complement may contribute to tissue damage and organ dysfunction of antibody-mediated diseases and ischemia-reperfusion conditions. Complement factors are being considered as targets for therapeutic intervention Objective We here characterize ARGX-117, a humanized inhibitory monoclonal antibody against complement C2. Methods The mode-of-action and binding characteristics of ARGX-117 were investigated in detail. Furthermore, its efficacy was analyzed in in vitro complement cytotoxicity assays. Finally, a PK/PD study was conducted in cynomolgus monkeys. Results Through binding to the Sushi-2 domain of C2, ARGX-117 prevents the formation of the C3 proconvertase, and inhibits classical and lectin pathway activation upstream of C3 activation. As ARGX-117 does not inhibit the alternative pathway it is expected not to affect the antimicrobial activity of this complement pathway. ARGX-117 prevents complement-mediated cytotoxicity in in vitro models for autoimmune hemolytic anemia and antibody-mediated rejection of organ transplants. ARGX-117 exhibits pH- and calcium-dependent target binding and is Fc-engineered to increase affinity at acidic pH to FcRn, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A two-dose regimen of 80 and 20 mg/kg separated by a week, resulted in profound reduction of classical pathway activity lasting for at least 7 weeks. Conclusion ARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathway while leaving the alternative pathway intact.

Halting targeted and collateral damage to red blood cells by the complement system

“… AIHA (CAD) Preclinical Effective in inhibiting C3 deposition in plasma of CAD patients in vitro Sanofi (Bioverativ, True North Therapeutics) [ 95 ] C1q ANX005 Monoclonal antibody IV Huntington disease, amythrophic lateral sclerosis, Guillan–Barre syndrome II Annexon [ 96 ] C2 ARGX-117 Monoclonal antibody IV n.s. Preclinical Argenx [ 97 ] PRO-02 Monoclonal antibody n.s. Ischemia-reperfusion injury or antibody-mediated disease Preclinical Prothix [ 98 ] C3 APL-9 Peptide IV Severe COVID-19 I/II Apellis, NCT04402060 Compstatin (AMY101, Cp40) Peptide SC or IV Gingivitis; COVID-19 II Amyndas, [ 83 , 85 , 86 ] Pegcetacoplan (APL-2) Peptide SC AIHA; PNH; age-related macular degeneration II (AIHA) and III Apellis [ 99 ] SLN500 RNAi n.s.…”

“…Currently, a phase II clinical study is underway in AIHA patients (ClinicalTrialsRegister.eu: 2012-003710-13/NL). The CP can also be targeted at other levels, using sutimlimab and BIVV020 to inhibit C1s and thus prevent C2 cleavage as described previously, or by using an mAb against C2 directly [ 86 , 87 , 97 ]. C2 especially is a promising target to block the CP and LP, as it has the lowest concentration of the CP and LP components and would therefore potentially require lower and/or less frequent dosage of inhibitors [ 8 ].…”

“…C2 especially is a promising target to block the CP and LP, as it has the lowest concentration of the CP and LP components and would therefore potentially require lower and/or less frequent dosage of inhibitors [ 8 ]. A recent study described ARGX-117 as an inhibiting mAb against C2, which successfully inhibited CP activity in cynomolgus monkeys [ 97 ].…”

Prevention of diabetes-associated fibrosis: Strategies in FcRn-targeted nanosystems for oral drug delivery

“…A range of additional hIgG Fc-engineered variants have been reported with increased persistence over the WT antibody when tested in hFcRn transgenic mice or non-human primates [165,166,[175][176][177][178][179][180][181][182], but these do not reach the same half-life values as that of YTE and LS.…”

Komplementinhibitoren: neue Therapeutika – neue Indikationen

“…ARGX-117 ist ein C2-Antikörper, der aktuell allerdings erst in einer Phase-I-Studie an gesunden Probanden bez. der Sicherheit überprüft wird [93]. Diese Befunde führten zur Entwicklung von Substanzen, welche gezielt den alternativen Weg der Komplementaktivierung hemmen.…”