intravenous immunoglobulin for patients with primary immunodeficiency

Intravenous immunoglobulin for patients with primary immunodeficiency

Presented by.. Suvanee Charoenlap , MD.

Outlines

• Introduction

• Physiology and pharmacokinetics of IVIG

• Mechanism of actions and indications

• IVIG for patients with primary immunodeficiency

Introduction

Intravenous immunoglobulin (IGIV)

: a highly purified antibody product prepared using pooled plasma from blood or plasma donations.

Endogenous IgG

Bayry J et al. Nat Clin Pract Rheumatol 2007;3(5)262–272

Exogenous IgG: commercial preparations of IGIV

• Derived from human plasma : whole blood donors or plasmapheresis

• Plasma pools range from 4000 L to > 50,000 L

• Required 1000 donors/lot (WHO original guidelines)

• Vary from normal endogenous IgG – The actual percentage of IgG

– different amounts of other proteins and immunoglobulins

– Fc integrity and function

– various excipients

Martin TD. International Immunopharmacology 2006;6:517-522

Properties of intravenous immunoglobulin

• Composition

– > 98% immunoglobulin G (IgG)

– > 90% monomeric IgG

– Traces of other immunoglobulins and serum proteins

– Addition of sugar, amino acids, or albumin stabilizes IgG from aggregation

Mark Ballow, Clinical immunology principle and practice; third edition: 1265 - 1280

• Intact Fc receptor important for biological function

– Opsonization and phagocytosis

– Complement activation

– Antibody-dependent cytotoxicity

• Normal half-life comparable to serum IgG

• Normal proportion of IgG subclasses

• Broad spectrum of antibodies to bacterial and viral agents

Properties of intravenous immunoglobulin

Mark Ballow, Clinical immunology principle and practice; third edition: 1265 - 1280

Plasma

Fractionation

Purification

Stabilization

Pathogen removal and inactivation

IVIG

Donor screening: Hx, PE, CBC, LFT Donor plasma testing : HIV-p24 Ag, HBsAg, and Ab to syphilis, HIV-1, HIV-2, HCV Inventory hold at least 60 days

Formulation and composition

Pathogen removal and inactivation

• Nanofiltration/ antibody-enhanced nanofiltration

• Solvent Detergent(S/D) treatment

• Low pH/elevated temperature incubation

• Vapour heat treatment

• Pasteurization

• Chromatography

• Cohn fractionation

• TSE (prion) removal

Berger M. Immunol Allergy Clin N Am 2008;28:413-437

Current quality control measures

for therapeutic IVIg

Characteristics QC measure Specifications Physical properties

Appearance Clear, no particles

pH

4–6, as specified by the manufacturer

Osmolality ≥240 mosmol/kg

Excipients Should be mentioned in the product label

Chemical properties

Total protein concentration γ-globulin content Immune aggregates Human origin identity test

≥30 g/l ≥95% ≤3% Positive

Viral inactivation components

Tri-n-butyl phosphate Polysorbate-80

Permissible level 10 μg/ml Permissible level 100 μg/ml

M. Radosevich & T. Burnouf, Vox Sanguinis (2010) 98, 12–28

Current quality control measures

for therapeutic IVIg Characteristics QC measure Specifications

Protein contaminants Anti-A and anti-B* Negative at HA titer of 1:64 (3% protein preparation)

Prekallikrein activator

≤3.5 IU/ml (3% protein preparation)

Total hemolytic complement levels

≤1 CH50 per mg of IgG

Viral marker tests

HBsAg, HIV p24 antigen, anti-HIV-1 antibodies, anti-HIV-2 antibodies and anti-HCV antibodies

All negative

Safety tests Bacterial sterility test Endotoxin assay

Sterile <0.5 IU/ml (5% protein preparation)

M. Radosevich & T. Burnouf, Vox Sanguinis (2010) 98, 12–28

Physiology and pharmacokinetics of IVIG

Serum half-lives of immunoglobulins in healthy adults

Bonilla FA. Immunol Allergy Clin N Am 2008;28:803-819

Pharmacokinetics of synthetic Ig

Intravascular

compartment Extravascular compartment

Catabolism Loss

IVIG SCIG


Pharmacokinetics of IVIg


Mechanism of action

Abbas et al. Cellular and Molecular Immunology. 7th edition.

Immunoglobulin

Ballow M. J Allergy Clin Immunol 2011; 127:315–323.

Innate immunity

• blockade of Fc receptors on macrophages of RE system

• restoration of idiotypic-antiidiotypic network

• neutralization of cytokines

• block binding of adhesion molecules on leukocytes to vascular endothelium

• inhibit complement uptake

• neutralize microbial toxins

• block Fas ligand-mediated apoptosis

• induce apoptosis with anti-Fas antibodies

• neutrophil apoptosis

• saturate the FcRn receptors

• induction of inhibitory FcγRIIB receptors on effector macrophages

Adaptive immunity

• neutralization of growth factors for B-cells ( B-cell activating factor)

• inhibit T-cell proliferative responses

• expand and/or activating a population of Treg cells

• downregulate the Th17 pathway

• inhibit the differentiation and maturation of dendritic cells

Modulating activities of IVIG

Ballow M. Curr Opin Allergy Clin Immunol 2014, 14:509–515

Indication

6 clinical indications in the USA with For FDA approval

1. Treatment of primary immunodeficiencies.

2. Prevention of bacterial infections in patients with hypogammaglobulinaemia and recurrent infection caused by

B-cell chronic lymphocytic leukaemia.

3. Prevention of coronary artery aneurysms in Kawasaki

disease.

4. Prevention of infections, pneumonia and acute graft versus

host disease (GVHD) after bone marrow transplantation.

5. Reduction of serious bacterial infection in children with HIV.

6. Increase of platelet count in ITP to prevent or control bleeding.

Orange JS et al. JACI 2006;117:S525-53

IVIG for primary and secondary immunodeficiency


Immunoglobulin replacement is indicated for all patients with the following diagnoses

• Severe combined immunodeficiency

• X-linked or autosomal recessive agammaglobulinemia

• Common variable immunodeficiency

• Other combined immunodeficiencies with a significant hypogammaglobulinemia or antibody production defect including but not limited to the following:

1. Wiskott-Aldrich syndrome

2. CD40 ligand deficiency (X-linked hyper-IgM syndrome)

3. Nuclear factor of B essential modifier deficiency

4. Ataxia-telangiectasia

5. DiGeorge syndrome

Bonilla FA. Ann Allergy Asthma Immunol 2005;94:S1-S63

Possible mechanisms of action of intravenous immunoglobulin (IVlG) in primary immunodeficiency

S. V. Kaveri et al. Clinical and Experimental Immunology,164 (Suppl. 2), 2–5

Uses of IVIG in other diseases

Group Diseases

Neurology Guillain Barre syndrome, Chronic inflammatory demyelinating polyradiculopathy (CIDP), Dermatomyositis and inflammatory myopathies, Myasthenia gravis, rare childhood epilepsy (Lennox gastaut seizure, Landau kleffner seizure), Opsoclonus myoclonus ataxia, PANDAS (Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection) OCD, anxiety, depression, emotional lability

Haematology ITP, Pure red cell aplasia, Pure white cell aplasia, Immune neutropenia, Immune haemolytic anemia.


Uses of IVIG in other diseases

Group Diseases

Dermatology Dermatomyositis, Toxic epidermal necrolysis, Blistering diseases, Immune urticaria, Atopic dermatitis, Pyoderma gangrenosum

Neonatology Haemolytic disease of newborn due to Rh and ABO incompatibility, Neonatal alloimmune thrombocytopenic purpura, Bacterial sepsis in preterms

Others Myocarditis, Systemic lupus erythematosus, Streptococcal toxic shock syndrome, Autoimmune uveitis


IVIG for patients with primary immunodeficiency

Dosing guidelines : IVIG

•Agammaglobulinemia or •Severe hypogammaglobulinemia Loading dose 1 g/kg IV •Dose - 300-400 mg/kg every 3 weeks (maximum 600 mg/kg)

- 400-500 mg/kg every 4 weeks (maximum 800 mg/kg)

•Interval : 2-4 weeks

Bonilla FA.Ann Allergy Asthma Immunol 2005;94:S1-S63

Dosing guidelines : IVIG

• High catabolism or more frequent infections

: Infusions every 2 to 3 weeks at lower dose

• Active infection – Dose should be halved to 200-300 mg/kg

– Repeated dose 2 weeks later to achieve a full dose

Barlow M. JACI 2008;122(5):1038-1039

Start • 0.01 ml/kg/minute

• (0.5 mg/kg/min of 5% solution)

Increase • double rate at 15-30 minutes interval

Maximum

• 0.08 ml/kg/minute

• (4 mg/kg/min of 5% solution)

• or up to maximum tolerated rate

IVIG infusion rate

Monitor: Vital signs and patient’s condition

before and 5-10 minutes after each rate change


Monitoring therapy


Adequate dose ?

Control of infection

and complication of underlying disease

Complication of therapy

q 6-12 mo.

- CBC

-LFT

-BUN/Cr

-UA

-Test for bloodborne disease

Measurement of trough serum IgG levels

• every 3 months until a steady-state is achieved

• then every 6 months if the patients is stable

IVIG dosage relates to IgG trough level in Meta-analysis

Orange, J.S., et. al., Clin Immunol 2010, 137:21-30

Relation of IgG trough level to Pneumonia

Orange, J.S., et. al., Clin Immunol 2010, 137:21-30

Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. JACI. 2008;122:201-1.

Adverse Reactions

Acute adverse reactions (during infusion)

Delayed adverse reactions (within 72 hrs)

Severity Clinical Interventions

Mild headache, malaise, fatigue, flushing, pruritus

• slow infusion • antihistamines and

NSAIDs

Moderate severe headache, dizziness or nausea, vomiting, myalgia, arthralgia, back pain, urticaria

• stop infusion • antihistamines and

NSAIDs • Consider steroids

Severe altered mental status, hypotension, bronchospasm, anaphylaxis.

• stop infusion • epinephrine,

antihistamines, steroids • supportive care or

resuscitation

Acute adverse reactions (during infusion)


Severity Clinical Interventions

Mild headache, malaise, fatigue, flushing, pruritus

• antihistamines and NSAIDs

Moderate to Severe

severe headache, dizziness or nausea, vomiting, myalgia, arthralgia, back pain, urticaria, aseptic meningitis syndrome.

• antihistamines and NSAIDs

• antimigraine medications

• Consider steroids

Delayed adverse reactions (within 72 hrs)


Bonilla FA. JACI 2008;122:1238-1239

• ≥ 20% of patients experience adverse effects • severe reactions occur in < 1% of them

Premedications


Route

Barlow M. JACI 2008;122(5):1038-1039

Barlow M. JACI 2008;122(5):1038-1039

Product consideration

Safety

Efficacy

Cost

• Formulation : Lyophilized Vs Liquid

• Volume : concentration

• Sodium

• Sugar

• Osmolality

• IgA content

• pH

Product consideration

Gelfand EW. International Immunopharmacology 2006;6:592-599

Age consideration Neonatal patients

pH concerns:

-local phlebitis

-Met. Acidosis

Limit volume infusion

Geriatric patients

Cardiac, Renal, Pulmonary

insufficiency

Sodium, Sugar and osmolar

load

Sodium, Sugar and osmolar load

Stabilizer considerations

Stabilizer Cautions

Sorbitol Hereditary fructose intolerance

Maltose Corn allergy

L-proline Hyperprolinemia

Glycine -

Does not increase glucose level in blood

Characteristics of Gammaglobulin Preparations Licensed in the United States


Properties of IVIG preparations currently available in the UK

S. Jolles et al.Clinical and Experimental Immunology, 142: 1-11

Flebogamma Gammaraas Liv-gamma

Formulation 5% liquid 5% liquid 5% liquid

Sodium content < 0.032 NA NA

Stabilizer D-sorbitol D-sorbitol Maltose

Osmolality (mosm/kg) 240-350 300 >240

IgG (g/L) >99% >98.5% > 95%

IgM (g/L) N.A. < 0.12 NA

IgA (g/L) < 0.05 < 0.07 NA

pH 5-6 3.8-4.4 4.0-7.4

Refrigeration 2-25°c 2-8°c 2-8°c

Plasma holding (days) 60 60 60

HIV PCR PCR ELISA

HBV PCR PCR ELISA

HCV PCR PCR PCR

Viral inactivation /removal Pasteurization, PEG

Nanofiltration Nanofiltration

Take home messages

Eight Guiding Principles for Effective Use of IVIG for Patients with Primary Immunodeficiency

Eight Guiding Principles for Effective Use of IVIG for Patients with Primary Immunodeficiency

1. Indication

2. Diagnoses

3. Frequency of IVIG treatment

4. Dose

5. IgG trough levels

6. Site of care

7. Route 8. Product

Thank you

intravenous immunoglobulin for patients with primary immunodeficiency

Health & Medicine

exogenous igg

immunoglobulin g igg

normal endogenous igg

monomeric igg traces

human plasma

antihcv antibodies

igg viral marker tests

endogenous igg bayry