Simple • Ready-to-use 10% liquid IVIg • Sucrose-free • Latex-free • Complimentary reimbursement hotline
Ready-to-Use Liquid Privigen™ at a Glance Low Annual Rate of Serious Bacterial Infections* Per Subject Year† (n=80 Subjects)
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0
Multiple Processing and Viral Inactivation/Removal* Steps
Annual Percentage of Sick Days vs Days Able to Perform Normal Activities
8.65 Days
2%
Sick Days 356.35 Days
• Depth filtration (CH9 Z+)*
• Cold ethanol precipitation
• Anion exchange chromatography
• Nanofiltration (to 20 nm)*
• Clarifying depth filtration
• Ultrafiltration
• Low pH incubation (inactivation under acidic conditions)*
• Octanoic acid fractionation
Purity
98%
Specification
Typical Value
Excipient
Concentration
IgG
≥98.0%
>99.2%†
L-proline
250 mmol/L (210-290 mmol/L)
Days Able to Perform Normal Activities
0.08
Composition
Protein IgG1
67.8% (61.7%-72.8%)
IgG2
28.7% (23.8%-35.3%)
Sodium
≤1 mmol/L
IgG3
2.3% (1.8%-2.9%)
Carbohydrate Stabilizers (Sucrose, Maltose, etc)
None
IgG4
1.2% (0.5%-2.8%)
IgA
≤25 mcg/mL
16-37 mcg/mL
Physicochemical and Pharmacokinetic Properties
* Results from case report forms
Aggregates
≤2.0%
<0.1% †
Parameter
Value
† Upper 1-sided 99% confidence interval: 0.203
Dimers
≤12.0%
4.4% at release, may increase to 8% during shelf-life†
Osmolality
320 mOsmol/kg (240-440 mOsmol/kg)
pH
4.8 (4.6-5.0)
Fragments
≤3% at release ≤6% at end of shelf-life
<1.9% at release, may increase to ≈ 5% during shelf-life†
Viscosity
~3 mPas at room temperature
Median half-life
36.6 days
Confirmed aSBIs‡
‡ Acute serious bacterial infections (aSBIs) defined as pneumonia, bacterial meningitis, bacteremia/septicemia, osteomyelitis/septic arthritis, and visceral abscess
†
Innovative • First and only proline-stabilized liquid Ig therapy • Only approved 10% liquid with 24-month room temperature storage • Low IgA content (≤25 mcg/mL)
†
Mean of 29 batches; Data on file. CSL Behring
Titers of Antibodies in Assays of Privigen™
What is proline?
Room Temperature Storage (months) 24
Privigen™ Gammagard Liquid*
9 6
Gamunex† 2
4
6
8 10 12 14 16 18 20 22 24
*Gammagard is a registered trademark of Baxter International, Inc.
Proline is one of the 20 naturally occurring amino acids that form human proteins. It can be synthesized by the human body or obtained from dietary sources. CSL Behring chose proline as the stabilizer for Privigen™ after extensive testing, analysis, and comparison to other amino acids, such as glycine.
Antibody
Range
Diphtheria antitoxin
3.8-7.3 IU/mL
Anti-streptolysin O
1310-2010 IU/mL
Anti-tetanus toxoid
26.9-52.1 IU/mL
Anti-pneumococcal capsular polysaccharide
595-1065 mcg/mL
Anti-hepatitis B surface antigen
3.0-10.1 IU/mL
Anti-poliomyelitis virus type 1
19-67 IU/mL
Anti-Haemophylus influenzae B
26.4-45.0 IU/mL
Anti-cytomegalovirus
51.2-116.8 IU/mL
†Gamunex is a registered trademark of Talecris Biotherapeutics, Inc.
Spec Sheet
7.1 Mechanism in Immunodeficiency
Figure 19. Blockade of Fcγ Receptors
is used by natural killer cells (NK cells) for removal of virus-infected cells or by eosinophils for killing of parasites.
In patients with primary and secondary immunodeficiencies, Privigen™ is used to provide the missing protective antibodies (replacement therapy). Privigen™ is manufactured from the pooled plasma of up to 60,000 blood donors and therefore includes a broad variety of antibody specificities against bacteria, viruses, other pathogens, and toxins to which the donor population has been exposed.92 Moreover, the antibodies in Privigen™ are structurally and functionally intact and their effector functions are fully operative. Binding to Fcγ receptors and activation of complement are important for the destruction of pathogens through phagocytosis or complement-mediated lysis and for the clearance of immune complexes. Antibody-dependent cellular cytotoxicity
Beyond its protective effect against infections, IgG has an important role in the regulation of the function of the whole immune system. Patients with primary immune deficiency often develop autoimmune disease. For example, patients with common variable immunodeficiency (CVID) often have immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia (AIHA). Intravenous immunoglobulin substitution therapy is believed to reduce the frequency of these autoimmune manifestations in PI.93
7.2 Mechanisms in Immunomodulation
Blocking of activating Fcγ receptors by infused IgG molecules may also inhibit antibody-dependent cellular cytotoxicity, as suggested for the protective effect of IVIg against demyelination in inflammatory neurologic diseases.96 Studies in a murine model, in which ITP was induced by an anti-platelet antibody, suggested another mechanism for
54
b. Activated macrophages phagocytose and destroy antibody-coated platelets.
c. A possible mechanism of action of IVIg in ITP is the blockade of Fcγ receptors, inhibiting the destruction of platelets coated with pathogenic autoantibodies.
d. Another hypothesis is that IVIg treatment decreases the expression of activating Fcγ receptors and/or increases the expression of the inhibiting FcRIIb. The macrophage response is thus shifted from activation to inhibition, and antibody-coated platelets are not phagocytosed. So far, this mechanism has only been demonstrated in mouse models of ITP.
down-regulation of phagocytosis. Platelet consumption was prevented by administration of IVIg or its Fc fragments and the effect was dependent on the surface expression of FcγRIIb on splenic macrophages. 97 The low affinity FcγRIIb (CD32) is an inhibitory receptor that blocks the clearance of platelets (Figure 19). 7.22 Modulation of Complement Activation and Other Anti-inflammatory Effects With its potent anti-inflammatory activity, IVIg has rapid effects on acute inflammation as has been shown in Kawasaki disease. 98,99 A major mechanism mediating IVIg anti-inflammatory effect is complement scavenging. Activated complement components, particularly C3b can bind to IgG. The infusion of a high dose of IVIg offers a multitude of binding sites that can re-direct the complement attack from the target organ (tissue recognized by pathogenic autoantibodies) to the IgG in the liquid phase. This effect has been shown in an animal model100 and in vitro and in vivo studies of patients with dermatomyositis.101,102
MOA
7.21 Blockade or Modulation of Fcγ Receptors The primary mechanism by which Privigen™ prevents the uncontrolled phagocytosis of autoantibody-coated platelets in ITP is considered to be a blockade of Fcγ receptors. This mechanism, which is supported by several lines of evidence, is illustrated in Figure 19. IVIg treatment has been shown to inhibit the clearance of RhD positive autologous erythrocytes coated with anti-RhD antibodies.94 Whether one of the three activating Fcγ receptors (FcγRI [CD64], FcγRIIa [CD32], FcγRIII [CD16]) is preferably inhibited by IgG, and to which degree monomeric, dimeric or complexed IgG (formed during or after infusion) are involved in IVIg-induced inhibition is still a matter of debate.89,95
a. In ITP, platelets are coated with pathogenic autoantibodies. These attach to splenic macrophages via activating Fcγ receptors.
Activated Fcγ receptor
Inhibitory Fcγ receptor
Autoantibody
IVIg
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Monograph
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