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1.
J Allergy Clin Immunol ; 147(4): 1420-1429.e7, 2021 04.
Article in English | MEDLINE | ID: mdl-32926878

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 sought to 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 pharmacokinetic/pharmacodynamic 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 the neonatal Fc receptor, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A 2-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. CONCLUSIONS: ARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathways while leaving the alternative pathway intact.


Subject(s)
Antibodies, Monoclonal/pharmacology , Complement C2/antagonists & inhibitors , Complement Inactivating Agents/pharmacology , Animals , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/pharmacokinetics , Calcium , Complement Activation/drug effects , Complement C2/analysis , Complement C2/metabolism , Complement Inactivating Agents/blood , Complement Inactivating Agents/pharmacokinetics , Epitope Mapping , Female , Humans , Hydrogen-Ion Concentration , Macaca fascicularis , Male
2.
J Innate Immun ; 6(3): 284-92, 2014.
Article in English | MEDLINE | ID: mdl-24192271

ABSTRACT

Activation of complement may cause severe tissue damage in antibody-mediated allograft rejection and other antibody-mediated clinical conditions; therefore, novel potent complement inhibitors are needed. Previously, we described binding of the inhibitory receptor LAIR-1 and its soluble family member LAIR-2 to collagen. Here, we investigated binding of LAIR-1 and LAIR-2 to the complement proteins C1q and MBL, which both have collagen-like domains, and evaluated the effect of this binding on complement function. We demonstrate specific binding of recombinant LAIR proteins to both C1q and MBL. Surface plasmon resonance experiments showed that LAIR-2-Fc protein bound C1q and MBL with the highest affinity compared to LAIR-2-HIS. We, therefore, hypothesized that LAIR-2-Fc is a potent complement inhibitor. Indeed, LAIR-2-Fc inhibited C4 fixation to IgG or mannan, reduced activation of C4 by aggregated IgG in plasma and inhibited iC3b deposition on cells. Finally, LAIR-2-Fc inhibited complement-mediated lysis of cells sensitized with anti-HLA antibodies in an ex vivo model for antibody-mediated transplant rejection. Thus, LAIR-2-Fc is an effective novel complement inhibitor for the treatment and prevention of antibody-mediated allograft rejection and antibody-mediated clinical conditions.


Subject(s)
Graft Rejection/prevention & control , Immune Complex Diseases/therapy , Immunotherapy , Receptors, Immunologic/metabolism , Recombinant Fusion Proteins/metabolism , Antibody-Dependent Cell Cytotoxicity/drug effects , Complement C1q/metabolism , Complement Pathway, Mannose-Binding Lectin/drug effects , Graft Rejection/immunology , HLA Antigens/immunology , Humans , Immune Complex Diseases/immunology , Immunoglobulin Constant Regions/genetics , Isoantibodies/metabolism , K562 Cells , Protein Binding/drug effects , Receptors, Immunologic/administration & dosage , Receptors, Immunologic/genetics , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/genetics
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