Session: 101. Red Cells and Erythropoiesis, Excluding Iron: Poster III
Hematology Disease Topics & Pathways:
autoimmune disorders, Fundamental Science, Research, autoimmune hemolytic anemia, Immune Disorders, Diseases, immunology, Biological Processes, Study Population, Animal model
This study demonstrates the in vitro and in vivo pharmacology of nipocalimab confirming concentration dependent FcRn engagement, inhibition of IgG recycling, and increased clearance of IgG consistent with the pharmacodynamics (PD) of FcRn engagement and IgG clearance observed in Phase 1 and 2 studies.
Methods: Primary human endothelial and villous trophoblast cells incubated in the presence of fluorescently-tagged IgG were treated with nipocalimab to assess its impact on IgG recycling by fluorescence microscopy and flow cytometry. After in vitro or in vivo nipocalimab administration, FcRn receptor occupancy (RO) was detected after cell fixation-permeablization with labeled nipocalimab. In vivo PD effects were assessed in human transgenic FcRn mice (Tg32, Jackson Labs) or cynomolgus monkeys due to nipocalimab’s specificity for primate FcRn. RO was measured over time in circulating monocytes in both species. Endogenous serum IgG in monkeys and exogenous human IgG in human transgenic mice were used to assess nipocalimab effect on IgG in vivo.
Results: Nipocalimab treatment of primary human target cells increased cellular IgG content by increasing lysosomal IgG consistent with inhibition of IgG recycling. Nipocalimab also demonstrated similar concentration-dependent inhibition of IgG recycling (IC50, 0.03 μg/mL) and FcRn saturation (EC50, 0.03 μg/mL) demonstrating a high degree of correlation between target engagement and PD effect. Saturation of FcRn binding by nipocalimab (full RO) occurred within 30’ to 2 hours at concentrations consistent with pharmacokinetic (PK) at full RO and the period of IgG lowering observed in clinical studies. In vivo, full RO also occurred rapidly within 2 hours of single i.v. infusions (dose ≥2 mg/kg) and was followed shortly by initiation of IgG lowering in both human FcRn transgenic mice and cynomolgus monkeys. PK and PD evaluation of single IV doses of nipocalimab in cynomolgus monkeys and human FcRn transgenic mice established consistent dose-, exposure-, and time-dependent relationships between PK, the PD effect on FcRn RO and the lowering of serum IgG concentrations. Duration of RO in peripheral blood monocytes in both preclinical species was dose-dependent, as was the duration of IgG clearance, suggesting a relationship between RO and maintenance of an increased IgG clearance rate. These pharmacological data demonstrate a high degree of correlation between nipocalimab-induced block in IgG recycling in in vitro cell models and in vivo PD effects (serum/plasma IgG lowering) seen in preclinical models.
Conclusion: These in vitro and in vivo preclinical studies demonstrate the in vitro and in vivo mechanism of action for nipocalimab. Nipocalimab is under clinical investigation for multiple IgG-mediated autoantibody disorders, including wAIHA. The close mechanistic relationship between nipocalimab concentration, FcRn occupancy and inhibition of IgG recycling resulting in rapid, deep and sustained IgG lowering in vivo is consistent between preclinical and clinical studies.
Disclosures: Choudhury: Janssen Research & Development, LLC: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Noël: Janssen Scientific Affairs, LLC: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Ebrahim: Janssen Pharmaceutical Companies of J&J: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Shu: Janssen Research & Development, LLC: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Ling: Janssen Research & Development, LLC: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Fattizzo: Alexion: Consultancy, Speakers Bureau; Sobi: Speakers Bureau; Amgen: Consultancy; Janssen: Consultancy; Momenta: Consultancy; Novartis: Consultancy, Speakers Bureau.
See more of: Oral and Poster Abstracts