SUMMARY

• Nipocalimab is an investigational, 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.^1-4
  • By interfering with the binding of IgG to FcRn, nipocalimab increases the lysosomal degradation of IgG, which reduces serum levels of total IgG and pathogenic IgG autoantibodies and alloantibodies that underlie multiple disease states.^1-5 
• Nipocalimab 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

BACKGROUND

• FcRn is a multifunctional atypical Fc-γ receptor (FcγR), present throughout life, that functions within intracellular endosomes.^2,6,7 It is the IgG transporter responsible for the long half-life (21 days) of IgG.^1,6 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.^2,7
• FcRn is found primarily within vesicles of various cells, including endothelial and immune cells.⁸ FcRn facilitates bidirectional transport of IgG across polarized epithelial barriers.⁶ 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).^1,6
• 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

• Nipocalimab is an investigational, 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: Nipocalimab Mechanism of Action: Inhibiting IgG Recycling).^1,9
  • When nipocalimab binds to FcRn, FcRn cannot bind and protect IgG, including pathogenic antibodies, from lysosomal degradation.^2,3,9 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.^2,9 Any FcRn-bound IgG is protected from destruction and released into circulation.^2,7
  • Although IgG levels decrease, they are not entirely eliminated, allowing likely preservation of cell-mediated immunity.^2,5 Nipocalimab has demonstrated up to an 85% reduction in circulating IgG in phase 1 and phase 2 studies.^1,4,10

• Nipocalimab 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: Nipocalimab Mechanism of Action: Inhibiting Placental IgG Transfer).^3,10,11

Binding Affinity and Specificity of Nipocalimab to FcRn

• Nipocalimab has a high binding affinity for FcRn at both endosomal pH (6.0) and physiological pH (7.4) which makes it less likely for nipocalimab to release from FcRn during the transition from the intracellular to extracellular compartments, allowing for occupancy of FcRn throughout the recycling pathway (see Table: Nipocalimab Binding Affinity to Human and Cynomolgus Monkey FcRn).^1,3,5,11

• Nipocalimab directly contacts the FcRn IgG (fraction crystallizable [Fc] domain) binding site which is a different location than the binding site for albumin (see Figure: X-Ray Crystallography of Nipocalimab Binding to FcRn).^3,5

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

• In cynomolgus monkey studies, nipocalimab demonstrated dose-dependent FcRn occupancy and IgG reduction (see Figure: Dose-Dependent FcRn Occupancy (A) and IgG Reduction (B) in Cynomolgus Monkey Studies).³

• Nipocalimab binds with specificity to FcRn but does not bind to the closely related protein human leucocyte antigen-2 (HLA-A2), which shares 45% sequence homology. In contrast, concentration-dependent binding is observed with anti-HLA-A2 mAb, as shown in Figure: Concentration-Dependent HLA-A2 Binding.⁵

Aglycosylated and Effectorless Design of Nipocalimab

• Nipocalimab 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.^5,12
  • Nipocalimab is aglycosylated at site N297A to disable FcγR and complement interaction.^5,12
  • Unlike fully Fc-glycosylated version of nipocalimab, aglycosylated nipocalimab 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.
  • Additionally, nipocalimab 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 Nipocalimab and Fc Glycosylated Nipocalimab.⁵

Preservation of Key Immune Functions

• In a phase 2 study evaluating the safety and efficacy of nipocalimab in adult patients with generalized myasthenia gravis (gMG), nipocalimab 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.^4,5,13 
• In a phase 2a study evaluating the efficacy and safety of nipocalimab 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.¹⁴ 

• In a phase 1 study in healthy volunteers, no effect was observed with nipocalimab 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.^5,15
• In an 8-week cynomolgus monkey immunotoxicity study, nipocalimab administered at doses up to 300 mg/kg did not impact the immune response to a neoantigen (keyhole limpet hemocyanin [KLH]) as assessed by production of anti-KLH IgM. Nipocalimab reduced levels of circulating anti-KLH IgG. See Figure: Nipocalimab Immune Response to Neoantigen (KLH) in Cynomolgus Monkeys.³

• • Nipocalimab 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 nipocalimab.⁵
  • Nipocalimab did not affect innate immune cells, CD8 T cell, or natural killer (NK) cell functions, as shown in Figure: Nipocalimab Preserves Key Innate Immune Cell Functions.⁵

• In vitro, there was no observed effect of nipocalimab on inhibition of CD4+ or CD8+ T cell antigen presentation as shown in Figure: CD4+ or CD8+ T Cell Antigen Presentation.⁵

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 17 December 2024.