Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans

Ulrichts, Peter; Guglietta, Antonio; Dreier, Torsten; Bragt, Tonke Van; Hanssens, Valérie; Hofman, Erik; Vankerckhoven, Bernhardt; Verheesen, Peter; Ongenae, Nicolas; Lykhopiy, Valentina; Enriquez, F. Javier; Cho, JunHaeng; Ober, Raimund J.; Ward, E. Sally; Haard, Hans de; Leupin, Nicolas

doi:10.1172/jci97911

Cited by 173 publications

(194 citation statements)

References 54 publications

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“…In the placebo group, the proportion of patients with bleeding decreased from 33.3% at baseline to a minimum of 25.0% at day 50. 33 Autoantibodies were identified in all patients in this study and were generally reduced following efgartigimod treatment. Additionally, the total IgG reduction did not reach the low thresholds previously reported to be associated with increased risk of infection in diseases causing hypogammaglobulinemia.…”

Section: Bleeding-related Eventsmentioning

confidence: 60%

“…30,31 Albumin is also recycled by FcRn, but binds at a site distinct from that of IgGs. 33 This natural ligand of FcRn has been engineered with ABDEG mutations, located in the CH2 and CH3 domain of the Fc fragment to increase affinity for FcRn whilst preserving its characteristic pH-dependent binding. 33 This natural ligand of FcRn has been engineered with ABDEG mutations, located in the CH2 and CH3 domain of the Fc fragment to increase affinity for FcRn whilst preserving its characteristic pH-dependent binding.…”

Section: Introductionmentioning

confidence: 99%

“…33 This natural ligand of FcRn has been engineered with ABDEG mutations, located in the CH2 and CH3 domain of the Fc fragment to increase affinity for FcRn whilst preserving its characteristic pH-dependent binding. 33 A Phase 2 study in patients with myasthenia gravis, an IgG autoantibody-mediated neuromuscular condition (NCT02965573), showed similar tolerability, and IgG reduction associated with clinically and statistically significant improvements on efficacy scales. 30,34,35 In healthy volunteers (NCT03457649), efgartigimod was well tolerated and induced a rapid reduction of total IgGs and all IgG subtypes.…”

Section: Introductionmentioning

confidence: 99%

“…32 Efgartigimod is a human IgG1 antibody Fc-fragment. 33 This natural ligand of FcRn has been engineered with ABDEG mutations, located in the CH2 and CH3 domain of the Fc fragment to increase affinity for FcRn whilst preserving its characteristic pH-dependent binding. Due to its increased affinity for FcRn at both acidic and neutral pH, efgartigimod outcompetes IgGs for binding to FcRn, resulting in accelerated degradation of endogenous IgGs.…”

Section: Introductionmentioning

confidence: 99%

“…30,34,35 In healthy volunteers (NCT03457649), efgartigimod was well tolerated and induced a rapid reduction of total IgGs and all IgG subtypes. 33 A Phase 2 study in patients with myasthenia gravis, an IgG autoantibody-mediated neuromuscular condition (NCT02965573), showed similar tolerability, and IgG reduction associated with clinically and statistically significant improvements on efficacy scales. 36 Targeted reduction of autoantibodies through FcRn blockade may prevent their pathogenic actions and represents a novel treatment modality in ITP.…”

Section: Introductionmentioning

confidence: 99%

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Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia

et al. 2019

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Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder, characterized by a low platelet count (<100 × 10 9 /L) in the absence of other causes associated with thrombocytopenia. In most patients, IgG autoantibodies directed against platelet receptors can be detected. They accelerate platelet clearance and destruction, inhibit platelet production, and impair platelet function,

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Section: Bleeding-related Eventsmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia

et al. 2019

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A Dual‐domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration

Jiang,

Chen,

et al. 2024

Advanced Science

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Chronic hepatitis B (CHB) remains a major public health concern because of the inefficiency of currently approved therapies in clearing the hepatitis B surface antigen (HBsAg). Antibody‐based regimens have demonstrated potency regarding virus neutralization and HBsAg clearance. However, high dosages or frequent dosing are required for virologic control. In this study, a dual‐domain‐engineered anti‐hepatitis B virus (HBV) therapeutic antibody 73‐DY is developed that exhibits significantly improved efficacy regarding both serum and intrahepatic viral clearance. In HBV‐tolerant mice, administration of a single dose of 73‐DY at 2 mg kg−1 is sufficient to reduce serum HBsAg by over 3 log10 IU mL−1 and suppress HBsAg to < 100 IU mL−1 for two weeks, demonstrating a dose‐lowering advantage of at least tenfold. Furthermore, 10 mg kg−1 of 73‐DY sustainably suppressed serum viral levels to undetectable levels for ≈ 2 weeks. Molecular analyses indicate that the improved efficacy exhibited by 73‐DY is attributable to the synergy between fragment antigen binding (Fab) and fragment crystallizable (Fc) engineering, which conferred sustained viral suppression and robust viral eradication, respectively. Long‐term immunotherapy with reverse chimeric 73‐DY facilitated the restoration of anti‐HBV immune responses. This study provides a foundation for the development of next‐generation antibody‐based CHB therapies.

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Clinical Pharmacology Approaches to Support Approval of New Routes of Administration for Therapeutic Proteins

Wang,

Ji,

Hariharan

et al. 2024

Clin Pharma and Therapeutics

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Intravenous or subcutaneous routes of administration (ROAs) are common dosing routes for therapeutic proteins. Eleven therapeutic proteins with approval for one ROA have subsequently received approval for a second ROA. The clinical programs supporting the second ROA consistently leveraged data from the first ROA and included studies that characterized the pharmacokinetics (PKs) of the drug administered by the new ROA to identify an appropriate dosage regimen. The selected dosing regimen was then further evaluated in clinical trials designed with various primary end points. All programs implemented model‐informed drug development approaches to ensure that the selected regimens would achieve comparable systemic exposures (PK‐based bridging) or pharmacodynamic (PD) responses (PD‐based bridging) as the reference ROA. To support the approval of a second ROA, these programs either demonstrated noninferiority in PK, PD, and/or clinical end points for the second ROA, or established efficacy and safety through a comparison to a placebo treatment. The accumulative examples showed that clinical trials which provided the primary evidence to support approvals of the second ROA generally demonstrated noninferiority in the systemic exposures regardless of being specified as an end point or not in the study protocols. The experience to date supports the use of PK‐ and PD‐based bridging approaches not only in the selection of dosing regimens for a second ROA to be tested in clinical studies, but also for providing evidence of effectiveness to support approval, when appropriate.

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Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans

Abstract: argenx BVBA.

Cited by 173 publications

References 54 publications

Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia

Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia

A Dual‐domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration

Clinical Pharmacology Approaches to Support Approval of New Routes of Administration for Therapeutic Proteins

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