Immunoglobulin therapy

Immunoglobulin Therapy
Puttatida Chetwong, MD.
10 September 2021
Division of Pediatric Allergy Immunology and Rheumatology
Department of Pediatrics, Faculty of Medicine
King Chulalongkorn Memorial Hospital

•Intravenous immunoglobulin (IVIG) preparations comprise the pooled
fraction of serum IgG from ~3,000–60,000 blood donors
•Generated in principle by a cold ethanol precipitation.
•Besides IgG, varying amounts of other immunoglobulin isotypes, most
notably IgA, can be found in the IVIG preparation.
•The clinical use of IVIG can be distinguished by the infused amount.
• For IgG replacement therapy to prevent microbial infections in
immunocompromised patients, doses of approximately 0.5 g per kg body weight
are used.
• For the suppression of autoimmune diseases, IVIG is infused at much higher
doses, which range from 1–3 g per kg body weight.
Nat Rev Immunol. 2013 Mar;13(3):176-89.
Overview of IVIG

Middleton’s allergy: principles and practice. 9th ed.
Structure of IgG
Nat Clin Pract Rheumatol. 2007 May;3(5):262-72.

Front Immunol. 2014 Oct 20;5:520.

IgG Receptors

Fc receptor expression patterns on human cells and biologic activity

Neonatal Fc receptor for IgG (FcRn)
• Endothelial cells and monocytes express the
neonatal Fc receptor for IgG (FcRn) that
internalizes serum IgG in an acidic
endosomal compartment.
• FcRn then recycles IgG molecules back into
circulation, effectively prolonging their half-life.
• Serum proteins without a recycling receptor
are internalized in lysosomes and degraded.

Cellular and Molecular Immunology, Abbas 9th Edition
Functions of Immunoglobulin

J Allergy Clin Immunol. 2011 Feb;127(2):315-23

• Benefit in ITP
• Fc receptor blockade of the reticuloendothelial system platelet counts
rapidly increase after administration of IVIG (dose 1-2 g/kg)
• Autoantibody-opsonized platelets are destroyed in spleen and liver by
means of FcᵧR-mediated phagocytic clearance.
• Fc receptor blockade on macrophages in spleen and in other parts of
the reticuloendothelial system using an mAb directed against the
FcᵧRIIIa receptor
Fc receptor blockade

Benefit in
• circulating autoantibody inhibitors to Factor VIII coagulant activity
• SLE
• Anti-neutrophil cytoplasmic antibody-associated vasculitis
• Guillain-Barre syndrome (GBS)
• Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
• Myasthenia gravis
Restoration of the idiotypic–anti-idiotypic
network

• IVIG demonstrated that low levels of autoreactive IgG antibodies that
recognize a wide array of self antigens
Self antigens:
• Cytokines
• Antigen-specific autoantibody
• CD95 (also known as FAS) or CD95 ligand (FASL)
• Sialic acid-binding immunoglobulin-like lectin 9 (SIGLEC9) expressed on
neutrophils
• SIGLEC8 expressed on eosinophils
• T cell-expressed antigens
• B cell-activating factor (BAFF), A proliferation-inducing ligand (APRIL)
• Adhesion molecules involved in leukocyte trafficking
Cytokine, autoantibody
neutralization

• Benefit in Kawasaki disease
• IVIG preparations contain neutralizing antibodies to staphylococcal derived enterotoxins
• Inhibit T-cell activation by these staphylococcal and streptococcal superantigens
• Inhibits production of cytokines by mononuclear cells (IL-1, TNF-a, TNF-b, and IFN-g by
PBMCs)
• Increasing production of IL-1 receptor antagonist
• Inhibits endothelial cell proliferation
• Downregulates mRNA expression of adhesion molecule (ICAM1, VCAM1), chemokine
Suppression of cytokine
production

• Benefit in Dermatomyositis, GBS, CIDP, Myasthenia gravis
• In vitro study: high levels of IgG could inhibit the uptake of C3 on
erythrocytes and inhibition of binding of C3b to antibodies on platelets
reduce C3b dependent opsonization of antibody-coated platelets by
macrophages of the RE system
• Decrease C3 and MAC deposition on endomysial capillaries and
decrease ICAM1 expression in muscle tissue
• Prevent complement mediated neuronal cell death
Inhibition of complement deposition on target
tissue

• TEN: death of the keratinocytes leads to large sections of the epidermis sloughing off
• Keratinocytes express Fas, and sera contain high circulating levels of Fas ligand
• IVIG contains anti-Fas antibodies prevent keratinocyte cell death by blocking the effects
of Fas ligand on Fas receptor on keratinocytes
• The anti-Fas antibodies in IVIG can enhance the apoptosis of human lymphocytes and
monocytes.
• Immunomodulating effects of anti-Fas antibodies might depend on the dose of IVIG and
the clinical disease state
• Low conc. (1-10 mg/mL) blocked anti-CD95–mediated neutrophil apoptosis
• High conc. (20-50 mg/mL) induced neutrophil death
Modulation of apoptosis

• Long term effects in ITP
• inhibited both B cell receptor–dependent and independent antigen presentation
(not mediated through the FcᵧRIIb receptor but was mediated by intracellular
events)
• Under specific conditions such as CD40 activation: IVIG promote differentiation
into IgG secreting B cells
• Contains other specific antibodies that react with number of cell-surface
determinants that could potentially modulate the immune response, such as the
αβ TCR, cytokine receptors, HLA determinants, CD5, CCR5, CD40, and sialic
acid–binding immunoglobulin-like lectins 8 and 9.
Modulation of B cells

• Benefit in Bullous pemphigoid, Arthritis, ITP
• FcRn: specialized receptor binds serum IgG,
protects IgG from degradation inside the lysosomes,
and returns IgG intact to plasma circulation
• Shorten the half-life of the autoantibody, more
rapidly eliminating it from the circulation
Saturation of FcRn

• Benefit in ITP, Rheumatoid arthritis, nephrotoxic
nephritis, chronic inflammatory demyelinating
polyneuropathy
• IVIG stimulates inhibitory FcᵧRIIb receptors
• IVIG enriched for sialylated glycan moiety
inhibitory or anti-inflammatory properties
Modulation of immunoregulatory function
through the Fc receptor
N Engl J Med. 2012 Nov 22;367(21):2015-25.

• Benefit in Kawasaki disease, GBS, autoimmune encephalomyelitis
• Suppress T-cell proliferative responses to mitogens by IVIG and
F(ab’)2 fragments to CD3 and CD28 stimulations
• Expanding and enhancing the function of FOXP3-positive Treg cells
increase production of IL-10, TGF-β, or effects on DC cells
• Inhibited maturation of monocytes into immature dendritic cells
Modulation of T cell immunoregulatory
function

Nat Clin Pract Rheumatol. 2007 May;3(5):262-72.

Manufacturing Process
Immunol Allergy Clin North Am. 2015 Nov;35(4):713-30.

https://www.sec.gov/Archives/edgar/data/1438569/000119312512270475/d367213d6k.htm

Nat Rev Rheumatol. 2011 Jun;7(6):349-59.

Immunol Allergy Clin North Am. 2008 Nov;28(4):803-19
Serum half-lives of immunoglobulins
Concentration dependence of IgG catabolism

Two-compartment model of IgG pharmacokinetics

Nat Rev Rheumatol. 2011 Jun;7(6):349-59.

Dose is absorbed slowly and redistributed
slowly, whereas concentration dependent
catabolism is ongoing
Serum IgG levels during SCIG therapy
(A) Weekly infusions. The IgG levels vary, on
average, less than 10% over the week in between
infusions.
(B) Biweekly infusions. The IgG level varies more
than it does with weekly infusions, but not as
much as with IVIG. The absorption is still blunted
in comparison to IVIG.

Clin Immunol. 2004 Jul;112(1):1-7.
IVIG vs SCIG

Ther Clin Risk Manag. 2010 Feb 2;6:1-10.

• The usual recommended dose of IGIV for immunodeficiency is 300 to 500 mg/kg given
every 3 to 4 weeks.
• The usual initial rate of infusion is 0.01 mL/kg/minute, which provides 0.5 or 1
mg/kg/minute of IgG depending whether a 5% or a 10% IGIV is used, respectively.
• The infusion rate can be doubled every 20 to 30 minutes until a rate of 0.08 mL/kg is
achieved.
• The infusion usually takes 2 to 4 hours.
• This may be longer if higher doses are given or shorter if the patient has tolerated a
more rapid rate or shorter interval between doses.
IVIG Dose
Transfus Med Rev. 2013 Jul;27(3):171-8.

• Higher doses of IGIV are used for autoimmune and inflammatory diseases, typically 1 to
2 g/kg per dose, and repeated at regular intervals.
• The daily dose of no more than 1 g/kg/day be given to most patients under age 60
and no more than 500 mg/kg/ day be given to patients over age 60 or to high risk patients.
• Patients requiring higher doses can get 500 mg/kg on subsequent days.
• The maximal dose is usually based on a weight of 70 kg, regardless of the patient’s
actual weight.
IVIG Dose

• The usual dose for SCIG is also 300 to 500 mg/kg/month, similar to the IGIV dose.
• Infusions are usually given weekly at 25% of the monthly dose.
• Thus a weekly dose of 100 mg/kg (400 mg/kg/month requires a subcutaneous infusion of
1.0 mL/kg of a 10% IG product or 0.5 mL/kg of a 20% IG product.)
• This is usually given slowly using a portable infusion pump.
• Multiple sites on the abdominal wall, thighs or arms can be used so that no more than 5
to 30 mL is given at a single site, depending on the patient’s weight.
• Because of the lessened risk of systemic side effects, SCIG can be given at home,
often by self-infusion, and without premedication
SCIG Dose

J Allergy Clin Immunol. 2017;139:S1-S46

Indications
J Allergy Clin Immunol. 2017;139:S1-S46

บัญชียาหลักแห่งชาติ 2563

Int Arch Allergy Immunol. 2014;164:151–66.

• Formulation (liquid, lyophilized)
• Volume load
• Sodium content
• Type of stabilizer
• Osmolality
• IgA content
• pH
Differences among Products

Stabilizers
• To minimize IgG aggregates
• Type of stabilizers:
– Amino acids: proline, glycine
– Sugars: sorbitol, maltose, glucose, sucrose
• Sugar contents associate with adverse events
– Osmotic nephrosis
– Sucrose  renal toxicity, renal failure/insufficiency
J Allergy Clin Immunol Pract 2013;1:558-66.

Volume load
• an important consideration in very young, elderly, cardiac impairment
Sodium content
• Varies widely in currently available preparations
• High salt contents  higher incidence of AEs & thromboembolic complications
Osmolality
• Sodium & sugar content
• Physiologic osmolality: 280-296 mOsm/kg of water
• Hyperosmotic state  thromboembolic complications
pH
• Optimum pH: 4.0-4.5 to remain IgG in unaggregated state
• Low pH may be associated with phlebitis
Int Immunopharmacol. 2006 Apr;6(4):592-9.

IgA Content
• IgG or IgE anti-IgA antibodies in patients with hypogammaglobulinemia
and absent serum IgA who are receiving IgA-containing IVIG can cause
severe reactions including anaphylaxis.
– CVID patient with serum IgA level <7 mg/dL are at highest risk.
• To minimize risk of severe reactions/anaphylaxis
– Use products with the lowest concentration of IgA
– Starting initial IVIG infusion slowly and gradually increase the
rate with subsequent infusions
Immunol Allergy Clin North Am. 2015;35(4):713-30.

Amount (gram) Volume (ml) ราคาขาย
5% LIV-Gamma 5 g 100 7,211
5% Flebogamma DIF 2.5 g 50 6,111
5% Flebogamma DIF 10 g 200 24,261
5% TRCS 2.5 g 50 2,790
5% TRCS 5 g 100 5,150
10% Kiovig 5 g 50 12,125
10% Kiovig 10 g 100 22,983
10% Gamunex-C 2.5 g 25 5,822
10% Gamunex-C 10 g 100 22,071
10% Privigen 5 g 50 11,501
20% Huzentra 4 g 20 14,821

J Allergy Clin Immunol. 2017;139:S1-S46.
IV

IV
IV/SC
SC

IM

Int Arch Allergy Immunol 2014;164:151–166

• 40-year-old female presenting with productive cough, fatigue, and postnasal drip for 3 days
• History:
- Repetitive sinusitis, otitis media, diarrhea, cystitis, and pneumonia since childhood
- Concomitant conditions: hypertension (155/90 mmHg),
pre-diabetes (fasting glucose: 120 mg/dL)
• Lab values:
- IgG 100 mg/dL (620-1400 mg/dL)
- IgA 30 mg/dL (80-350 mg/dL)
- IgM 25 mg/dL (45-250 mg/dL)
• Diagnosis: common variable immune deficiency
What to consider in this patient?

Immunoglobulin therapy

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