SUMMARY

• The company cannot recommend any practices, procedures, or usage of IMAAVY that deviate from the approved labeling.
• Please refer to the local labeling for relevant information regarding the mechanism of action of IMAAVY.
• IMAAVY is a high affinity, fully human, aglycosylated, effectorless, monoclonal antibody (mAb) and is believed to selectively block the neonatal fragment crystallizable receptor (FcRn) thereby reducing levels of circulating immunoglobulin G (IgG) antibodies.^1-5
  • By interfering with the binding of IgG to FcRn, IMAAVY increases the lysosomal degradation of IgG and blocks IgG recycling, which reduces serum levels of total IgG and pathogenic IgG autoantibodies and alloantibodies that underlie multiple disease states.^1-6 
• IMAAVY lowers IgG levels while preserving key innate and adaptive cellular immune functions, such as production of antigen-specific immunoglobulin M (IgM) and IgG in response to neoantigen immunization.^5,6

BACKGROUND

• FcRn is a multifunctional atypical Fc-γ receptor (FcγR), present throughout life, that functions within intracellular endosomes.^2,7,8 It is the IgG transporter responsible for the long half-life (21 days) of IgG.^1,7 During FcRn recycling, IgG and other plasma proteins are ingested into cells through pinocytosis.² Internalization and acidification of the endosome occurs, during which FcRn binds IgG to retain it within the endosome and divert it from degradation in lysosomes.^2,8
• FcRn is found primarily within vesicles of various cells, including endothelial and immune cells.⁹ FcRn facilitates bidirectional transport of IgG across polarized epithelial barriers.⁷ By doing so, FcRn can deliver IgG from the tissue space in the lumen and transport it back to the lamina propria across a variety of tissue types. This process also facilitates the transfer of maternal IgG across the placenta to the fetus during pregnancy. FcRn binds IgG and albumin, protecting them from lysosomal degradation by recycling them to the cell surface. This binding occurs at endosomal pH (typically pH<6), but not at extracellular pH (pH~7.5).^1,7
• FcRn blockade reduces circulating IgG levels including pathogenic IgG and may potentially improve various autoimmune conditions, including neurological, hematological, and rheumatological diseases, as well as pregnancy-related alloimmune complications.^1,2

MECHANISM OF ACTION

Overview

• IMAAVY is a high-affinity, fully human, effectorless monoclonal IgG1 anti-FcRn antibody that reduces serum IgG concentrations by inhibiting FcRn-mediated IgG recycling while preserving IgG production (see Figure: IMAAVY Mechanism of Action: Inhibiting IgG Recycling).^1,5,10
  • When IMAAVY binds to FcRn, FcRn cannot bind and protect IgG, including pathogenic antibodies, from lysosomal degradation.^2,3,5,10 Blocking of the IgG binding site of FcRn allows for inhibition of IgG recycling and increased clearance of IgG as unbound IgG is degraded, thereby inhibiting their sorting into vesicles and recycling back into circulation.^2,5,10 Any FcRn-bound IgG is protected from destruction and released into circulation.^2,5,8
  • Although IgG levels decrease, they are not entirely eliminated, allowing likely preservation of cell-mediated immunity.^2,5,6IMAAVY has demonstrated up to an 85% reduction in circulating IgG in phase 1 and phase 2 studies.^1,4,5,11

• IMAAVY can also inhibit the placental transfer of IgG from mother to fetus in pregnancy to reduce levels of circulating maternal IgG alloantibodies due to high-affinity binding to FcRn at both intracellular and extracellular pH, thereby preventing release from FcRn during transfer process (see Figure: IMAAVY Mechanism of Action: Inhibiting Placental IgG Transfer).^3,5,11,12
• In addition to reducing maternal alloantibody transfer in pregnancy, the high binding affinity of IMAAVY at both acidic and neutral pH ensures persistent FcRn engagement throughout placental transcytosis, thereby limiting fetal exposure to pathogenic IgG.⁵ 

Binding Affinity and Specificity of IMAAVY to FcRn

• The high binding affinity values were confirmed using surface plasmon resonance and cell-based assays.⁵  IMAAVY has a high binding affinity for FcRn at both endosomal pH (6.0) and physiological pH (7.4) which makes it less likely for IMAAVY to release from FcRn during the transition from the intracellular to extracellular compartments, allowing for occupancy of FcRn throughout the recycling pathway (see Table: IMAAVY Binding Affinity to Human and Cynomolgus Monkey FcRn).^1,3,5,6,12

• IMAAVY showed concentration-dependent binding to FcRn at pH 7.4, with half-maximal effective concentration (EC₅₀) values of 0.85 μg/mL (95% CI: 0.74-0.98) for human and 0.68 μg/mL (95% CI: 0.58-0.79) for cynomolgus monkey FcRn. It also exhibited concentration-dependent inhibition of IgG binding to human and cynomolgus monkey FcRn, with half-maximal inhibitory concentration (IC₅₀) values of 3.2 μg/mL (95% CI: 2.52-4.16) and 4.6 μg/mL (95% CI: 3.98-5.32), respectively, at an IgG concentration of 10 μg/mL.⁵ 
• X-ray crystallography reveals that IMAAVY antigen binding fragment (Fab) binds directly to the IgG binding site on FcRn, with a large interface area of 1017.5 Ų, which is a different location than the binding site for albumin,⁵ see Figure: X-Ray Crystallography of IMAAVY Binding to FcRn.^3,6
• The crystal structure on the x-ray crystallography reveals a novel binding mode that maximizes the interaction between IMAAVY Fab heavy and light chains and FcRn. The binding epitope is mostly located on the α-chain of FcRn.⁵

• Fluorescence microscopy in human umbilical vein endothelial cells (HUVECs) showed that treatment with IMAAVY resulted in extensive co-localization of fluorescently labeled IgG (DyLight-488) with a lysosomal marker (dextran Alexa Fluor [AF]594), indicating IgG degradation via lysosomal trafficking. In contrast, isotype control IgG showed minimal lysosomal co-localization, confirming that IMAAVY blocks IgG–FcRn binding and promotes IgG degradation.⁵
• In human aortic endothelial cells (HAECs), no increase in intracellular albumin (AF647-labeled) was observed with IMAAVY concentrations up to 142 μg/mL, whereas a marked increase occurred with ADM31, an FcRn blocker that interferes with albumin binding. These findings demonstrate that IMAAVY selectively inhibits IgG recycling without affecting albumin homeostasis.⁵

Concentration- and Dose- Dependent FcRn Occupancy and IgG Reduction of IMAAVY

• In HAECs, concentration-dependent FcRn occupancy and inhibition of IgG recycling was observed with IMAAVY (see Figure: Concentration Dependence for FcRn Occupancy and Inhibition of IgG Recycling in Human Endothelial Cells).³

• In human FcRn transgenic (Tg32) mice, IMAAVY demonstrated a dose- and time-dependent relationship between FcRn occupancy and degradation of circulating human IgG. Following a single intravenous (IV) dose (0.2-100 mg/kg), doses ≥2 mg/kg achieved >90% FcRn occupancy in circulating monocytes, with the 100 mg/kg dose sustaining this level for up to 72 hours. Correspondingly, a >90% reduction in IgG levels was observed in the 100 mg/kg group, compared to ~40% in the control group. IgG degradation was only evident when FcRn occupancy was present, confirming that FcRn saturation drives IgG clearance in vivo.⁵
• In cynomolgus monkeys, single-dose IV administration of IMAAVY (0.2-100 mg/kg) resulted in dose-dependent, nonlinear pharmacokinetics, consistent with target-mediated drug disposition (TMDD), see Figure: Dose-Dependent FcRn Occupancy (A) and IgG Reduction (B) in Cynomolgus Monkey Studies.³ Doses ≥20 mg/kg achieved >90% FcRn occupancy within 4 hours, with the 100 mg/kg dose maintaining >80% occupancy for ~192 hours. These levels were associated with >75% serum IgG reduction, with no reduction observed in the animals in control group. After IMAAVY clearance, IgG levels returned to baseline.⁵

Aglycosylated and Effectorless Design of IMAAVY

• IMAAVY was designed with no effector function (via aglycosylation), to help eliminate the potential for inflammatory and tissue-destructive side effects mediated by immune effector cells and complement engagement.^5,6,14
  • IMAAVY is aglycosylated at site N297A to disable FcγR and complement interaction.^5,6,14
  • Unlike fully Fc-glycosylated version of IMAAVY, aglycosylated IMAAVY does not activate luciferase activity in FcγRIIIa- or FcγRIIa-transfected Jurkat cells when co-cultured with FcRn-human embryonic kidney (HEK) target cells in the antibody-dependent cellular cytotoxicity or antibody-dependent cellular phagocytosis reporter assays.^5,6,14
  • Additionally, IMAAVY does not induce complement fixation upon culture with FcRn-HEK target cells and normal human serum in the complement-dependent cytotoxicity assay as summarized in Figure: Effector Functions of IMAAVY and Fc Glycosylated IMAAVY.⁶

Preservation of Key Immune Functions

• In a phase 2 study evaluating the safety and efficacy of IMAAVY in adult patients with generalized myasthenia gravis (gMG), IMAAVY reduced total IgG and IgG subclasses 1-4. There was no observed effect seen with other immunoglobulin classes including immunoglobulin A (IgA), immunoglobulin E (IgE), and IgM.^4-6,15 
• In a phase 2a study evaluating the efficacy and safety of IMAAVY in adults with moderate to severe rheumatoid arthritis, changes from baseline in IgA, IgE, and IgM are summarized in Figure: Change from Baseline at Trough in IgA, IgE, and IgM.¹⁶ 

• In a phase 1 study in healthy volunteers, no effect was observed with IMAAVY on plasma cytokines (interferon-γ [IFN-γ], tumor necrosis factor-α [TNF-α], interleukin [IL] 2, IL6), 50% hemolytic complement (CH50), complement component 3 (C3), C4, IgM, IgA or IgE.^5,6,17
• In a cynomolgus monkey immunotoxicity study, IMAAVY administered at doses up to 300 mg/kg weekly did not impact the immune response to a neoantigen (keyhole limpet hemocyanin [KLH]) as assessed by production of anti-KLH IgM. There were no treatment-emergent effects on lymphocyte populations, cytokine levels, NK cell activity, monocyte and granulocyte function, or cytotoxic T cell degranulation. IMAAVY reduced levels of circulating anti-KLH IgG.⁵ See Figure: IMAAVY Immune Response to Neoantigen (KLH) in Cynomolgus Monkeys.³

• IMAAVY also showed no effect on 13 plasma cytokines, including ILs (IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-12/23 [p40], IL-13, IL-17), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN-γ, and TNF-α. Additionally, immune cell counts, relative percentages, and immune cell surface marker expression in various lymphocyte subsets (eg, all lymphocytes, B cells, cluster of differentiation (CD)4+ or CD8+ T cells, specific T cell subsets) were not affected by IMAAVY.⁶
• IMAAVY did not affect innate immune cells, CD8 T cell, or natural killer (NK) cell functions, as shown in Figure: IMAAVY Preserves Key Innate Immune Cell Functions.⁶

• In vitro, there was no observed effect of IMAAVY on inhibition of CD4+ or CD8+ T cell antigen presentation as shown in Figure: CD4+ or CD8+ T Cell Antigen Presentation.⁶

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 23 June 2025.