Immune Globulin: The Miracle Product

1
Immune Globulin The Miracle Product

• Mark C. Hannibal, MD, PhD
• University of Washington School of Medicine
• Department of Pediatrics
• Division of Genetics and Developmental Medicine

2
Outline

• Review of the immune system antibodies
• Passive immunity
• History of immune globulin therapy
• Present state of immune globulin therapy
• Products
• Indications
• Adverse events
• Practical considerations

3
Immune Function

• Two interrelated activities
• Recognition
• Response

4
Immune Response

• Starts when foreign structure (antigen) is
  recognized
• Involves a variety of cellular and humoral
  mediators
• Process known as effector response

5
Antigens

• Molecules foreign to blood and other body fluids
• Stimulate production of antibodies
  (immunoglobulins)
• Combine specifically with the antibodies produced

6
Types of Immune Response

• Innate or inborn (nonspecific)
• Inherited defense mechanisms
• Adaptive or acquired (specific)
• Prior exposure to antigen necessary
• Passive
• Supplied via donor

7
Innate Immune Response

• First line of defense against pathogens
• Nonspecific immunity
• Present from birth
• Defenses include
• Physical barriers
• Cellular mediators
• Humoral mediators

8
Adaptive Immune Response

• Acquired in response to specific stimuli
• Differs from innate response
• Antigen specificity
• Diversity
• Immunologic memory
• Self and nonself recognition
• Defenses include
• Cellular mediators
• Humoral mediators

9
Adaptive Cellular Mediators

• B-lymphocytes
• T-lymphocytes
• Helper cells
• Suppressor cells
• Cytotoxic cells
• Surface receptors recognize antigens
• Lymphocyte pool has ability to recognize up to
  1016 antigens

10
Adaptive Humoral Mediators

• Cytokines
• Lymphokines
• Immunoglobulins (antibodies)
• IgG
• IgM
• IgA
• IgD
• IgE

11
Primary Adaptive Response

• First exposure to pathogen
• Immune response often insufficient to combat
  disease
• Latent period of 5 to 10 days before measurable
  amounts of specific antibodies appear in blood

12
Secondary Adaptive Response

• Subsequent exposure to same antigen
• Antibody production is much more rapid
• Provides long-lasting protection
• Demonstrates memory of adaptive response

13
Primary and Secondary Immune Response
Secondary Response
IgG
Plasma Antibody Concentration
Primary Response
IgM
Time after exposure to antigen
Adapted from Wei-Chiang S, Louie SG. Immunology
for Pharmacy Students. 1999.
14
Optimal Immune Response

• Both cellular and humoral mediators needed
• Both innate and adaptive responses utilized

15
Immune Response
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B-lymphocytes

• Antigen-presenting cell
• Presents antigen to T cells
• Derived from bone marrow CD34 stem cells
• Expresses only a single specific antibody
• Major function is antibody production
• Humoral immunity

B Cell
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B-Cell Activation

• Two required steps
• Binding of antigen to surface immunoglobulin
• Secretion of B cell growth factors by activated
  CD4 cells (IL-4, -5, -6)

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Activated B Cells

• Plasma cells
• Produce large amounts of antibody
• Memory cells
• Respond to subsequent pathogen encounters
• Quicker, more vigorous response

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Target Extracellular Organisms
Inflammatory CD4 Cell (TH2)
TH2

• Proliferation
• Antibody Synthesis
• Memory

CD4
CD40L
TCR
CD40
MHC Class II
Y
Antigen
Antigen-presenting cell (B Cell)
B
Adapted from Israels LG, Israels ED. Mechanisms
in Hematology. 1996.
20
Adaptive Humoral Response
21
Adaptive Humoral Response
Cells involved in adaptive humoral response

• B cells
• Plasma cells
• Activated B cells that secrete antibodies
• Memory cells
• Adaptive immunity

22
Immunoglobulins (Ig)

• Also known as antibodies
• Neutralize and opsonize pathogens
• Found in human serum
• Found in the gamma globulin class of plasma
  proteins, produced by B cells
• Different Ig have different structures and
  specific functions
• Bind to antigen

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Ig Isotypes

• Classes
• Immunoglobulin G (IgG)
• Immunoglobulin M (IgM)
• Immunoglobulin A (IgA)
• Immunoglobulin D (IgD)
• Immunoglobulin E (IgE)

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Ig Production

• Activated B cell transforms into plasma cell
• Plasma cell synthesizes Ig (2000/sec)
• Synthesis of Ig
• Packed in endoplasmic reticulum
• Channeled through Golgi apparatus
• Glycosylated
• Transported to surface for secretion

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Antibody Structure

• 4 polypeptide chains
• 2 light chains
• 2 heavy chains
• Fab region
• Fab fragment antigen binding
• Specific binding site for antigen
• Fc region
• Fc fragment crystalline
• Interacts with Fc receptor
• Hinge region
• Flexibility for Ag binding

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Antibody Domain Function

• V domain (VL - VH)
• Antigen binding
• C1 domain (CL - CH1)
• Coupling of L and H chains
• CH2
• Interacts with complement
• CH3
• Attaches to Fc receptors
• Activates
• Macrophages
• PMN
• Platelets

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IgG

• Most prevalent antibody
  (80 serum antibody)
• Four subclasses
• IgG1 and IgG3
• Primarily recognize protein antigens
• IgG2 and IgG4
• Bind carbohydrate antigens
• Only antibody that crosses placenta
• Produced on second antigen exposure

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IgM

• Found on B-cell surface
• Pentamer (5 monomers)
• No Fc portions exposed
• Phagocytic cells cant bind pathogens opsonized
  by IgM
• Excellent activator of complement cascade
• Classic pathway
• Produced during first exposure to antigen

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IgA

• Found in fluid secretions
• Tears
• Saliva
• Nasal solution
• GI mucus
• Dimeric form
• Linked with secretory component
• Secreted in breast milk

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IgD

• Function not fully understood
• Found on B-cell surface during different stages
  of maturation
• Possible involvement in cell differentiation

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IgE

• Least common serum isotype
• Most IgE bound to IgE Fc receptor on mast cells
• Antigen binding to IgE releases inflammatory
  substances
• Histamine
• Pathogenesis of hay fever, allergic asthma

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Ig Subclass Comparison


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Characteristics of Ig Classes
Adapted with permission from Wick M, Wick M,
Heberger S, Simon H, Fateh-Moghadam A.
Infusionsther Transfusionmed. 199623(Suppl
4)55-59.
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Antibody Class Switch

• Primary response to antigen is IgM
• Naïve B cells
• Secondary antibody response is IgG
• Memory cells
• Class switch provides IgG and IgA antibodies
• IgG moves outside intravascular space
• IgG crosses placenta
• IgA transported to mucosal surfaces

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Passive Immunity

• Immune protection produced by transfer of
  antibodies to a recipient from a donor
• Donor has been actively immunized
• Occurs naturally from mother to fetus during
  pregnancy and mother to infant during nursing
• Short-lived protection

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Immune Globulin Drug name for passive immunity
products

• History of passive immunity transfer
• Current brands and production
• FDA-approved useOn-Label
• Off-Label use and evidence for efficacy
• Safety and side effects
• Practical considerations

37
History of Transfer of Passive Immunity

• Late 19th Century, von Behring and Kitasato
  demonstrate antitoxin effect of blood drawn from
  rabbits immune to tetanus toxins
• This was soon applied to humans
• By 1938, immunoglobulins were being isolated from
  pooled human serum

38
Cohn Cold-Ethanol Fractionation

• Large scale plasma fractionation during World War
  II allowed stable storage
• Plasma cooled to 0C, ethanol and buffer added,
  and four protein fractions were precipitated out
  of solution
• Cohn fraction II contained most antibodies
• Intramuscular administration protected against
  measles and hepatitis A

39
Immune Globulin Treatment for Primary
Immunodeficiency

• 1952 Bruton describes agammaglobulinemia

40
Swiss Red Cross Laboratories

• 1960s Barundun and others prepared IgG for
  intravenous use
• low pH (acidic) and traces of pepsin protease to
  inhibit reaggregation
• Prevent anaphylactic reactions to IVIG

41
1980s FDA Approval of IVIG

• Initial three forms of IVIG
• Sandoglobulin (Sandoz-Novartis) fractionated and
  lyophilized at low pH 4
• Gamimune N (Cutter-Bayer) fractionated at pH
  4.25 and stabilized with maltose
• Gammagard (Baxter-Travenol) cold ethanol
  fractionation then ion-exchange chromatography

42
Growth of IVIG Usage

• From 1992 to 2003, production tripled from 19.4
  to 52.6 tons
• Up to 8 different products available
• Changing product line as Red Cross got out of the
  market, Octapharma entered, phase out of old
  products and introduction of new ones by
  established manufacturers

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Carimune NF ZLB-Behring

• Descendent of Sandoglobulin
• Labeled for Primary Immune Deficiency, Acute and
  Chronic ITP
• USA donors
• pH 4 with pepsin, nanofiltration
• 5 sucrose (3 IgG reconstitution)
• Lyophilized

44
Gamunex Talecris

• Labeled for Primary Humoral Immunodeficiency and
  ITP
• USA donors
• Caprylate and chromatography purified
• No sugar content
• 10 IgG Liquid

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Gammagard Liquid Baxter

• Labeled for Primary Immune Deficiency
• Paid donor pool
• Solvent/detergent treated, nanofiltration, low pH
  
• No added sugar
• Latex free packaging
• 10 IgG Liquid

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Gammagard S/D Baxter

• Labeled for Primary Immune Deficiency, ITP,
  Chronic Lymphocytic Leukemia, Kawasaki syndrome
  (disease)
• Paid donor pool
• Solvent/detergent treated, ultrafiltration,
  ion-exchange chromatography
• 4 glucose (10 IgG reconstitution) sugar content
• Lyophilized
• Packaging contains latex
• Lowest IgA content of immune globulins

47
Flebogamma Grifols

• Labeled for Primary Immune Deficiency Disorders
• USA donors
• PEG precipitation, ion-exchage chromatography,
  pasteurization
• 5 D-Sorbitol sugar alcohol content
• 5 IgG Liquid

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Octagam Octapharma

• Labeled for Primary Immune Deficiency
• USA non-remunerated donors
• Solvent/Detergent, pH 4 treatment
• 10 Maltose sugar content
• 5 IgG Liquid

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Vivaglobin ZLB Behring

• Labeled for Primary Immune Deficiency
• 16 IgG liquid for subcutaneous use
• Glycine stabilized no sugar

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GamaSTAN S/D Talecris

• Formerly Baygam produced by Bayer
• Labeled for Hepatitis A, measles, rubella and
  varicella prophylaxis, and hypogammaglobulinemia
  and agammaglobulinemia
• 16 IgG liquid for intramuscular use
• Glycine-stabilized no sugar
• Can be used subcutaneously (off-label)

51
FDA-Approved Indications for IVIG

• Primary Immune Deficiency
• Idiopathic Thrombocytopenic Purpura
• Kawasaki Disease
• B-cell Chronic Lymphocytic Leukemia
• HIV Infection
• Bone Marrow Transplantation

52
Immune Globulin Use in Primary and Secondary
Immune Deficiency

• Definitely Beneficial
• Primary immune defects with absent B cells
• Hypogammaglobulinuria and impaired specific
  antibody production
• Probably Beneficial
• Chronic Lymphocytic Leukemia with low IgG and
  history of infections
• Prevention of infections in HIV-infected children
• Primary immune defects with normogammaglobulinemia
  and impaired specific antibody production

53
Immune Globulin Use in Primary and Secondary
Immune Deficiency

• Might Provide Benefit
• Prevention of neonatal sepsis
• Unlikely to be Beneficial
• Isolated IgA deficiency
• Isolated IgG4 deficiency

54
Immune Globulin Use in Autoimmunity

• Definitely Beneficial
• Graves ophthalmopathy
• Idiopathic thrombocytopenic purpura
• Probably Beneficial
• Dermatomyositis and polymyositis
• Autoimmune uveitis

55
Immune Globulin Use in Autoimmunity

• Might Provide Benefit
• Severe rheumatoid arthritis
• Autoimmune diabetes mellitus
• Posttransfusion purpura
• Vasculitides and antineutrophil antibody
  syndromes
• Autoimmune neutropenia
• Autoimmune hemolytic anemia
• Autoimmune hemophilia
• Systemic lupus erythematosus
• Fetomaternal alloimmune thrombocytopenia
• Neonatal isoimmune hemolytic jaundice
• Unlikely to be Beneficial
• Inclusion body myositis
• Antiphospholipid antibody syndrome

56
Immune Globulin Use in Neuroimmunologic Disorders

• Definitely Beneficial
• Guillain-Barré syndrome
• Chronic inflammatory demyelinating polyneuropathy
• Multifocal motor neuropathy
• Probably Beneficial
• Lambert-Eaton myasthenic syndrome
• IgM antimyelin-associated glycoprotein
  paraprotein-associated peripheral neuropathy
• Myasthenia gravis
• Stiff-man syndrome

57
Immune Globulin Use in Neuroimmunologic Disorders

• Might Provide Benefit
• Monoclonal gammopathy multiple sclerosis
• Intractable childhood epilepsy
• Rasmussen syndrome
• Acute disseminated encephalomyelitis
• HTLV-1-associated encephalomyelitis
• Cerebral infarction with antiphospholipid
  antibodies
• Demyelinative brainstem encephalitis
• Lumbosacral or brachial plexitis
• Paraproteinemic neuropathy
• Opsoclonus myoclonus
• Postinfectious cerebellar ataxia
• Acute idiopathic dysautonomia

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Immune Globulin Use in Neuroimmunologic Disorders

• Unlikely to be Beneficial
• Demyelinating neuropathy associated with
  monoclonal IgM
• Adrenoleukodystrophy
• Amyotrophic lateral sclerosis
• Polyneuropathy, organomegaly, endocrinopathy,
  monoclonal gammopathy, and skin changes (POEMS)
  syndrome
• Paraneoplastic cerebellar degeneration, sensory
  neuropathy or encephalopathy

59
Immune Globulin Use in Infectious and
Infection-Related Diseases

• Definitely Beneficial
• Kawasaki disease
• CMV-induced pneumonitis in solid organ
  transplants
• Probably Beneficial
• Neonatal sepsis
• Rotoviral enterocolitis
• Bacterial infections in lymphoproliferative
  diseases
• Streptococcal toxic shock
• Enteroviral meningoencephalitis

60
Immune Globulin Use in Infectious and
Infection-Related Diseases

• Might Provide Benefit
• Postoperative sepsis
• RSV lower respiratory tract infection
• Pseudomembranous colitis
• Campylobacter species-induced enteritis
• Unlikely to be Beneficial
• Chronic fatigue syndrome
• Acute rheumatic fever
• Viral load in HIV infection

61
Miscellaneous Use of Immune Globulin

• Definitely Beneficial
• None
• Probably Beneficial
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome

62
Miscellaneous Use of Immune Globulin

• Might Provide Benefit
• Severe, persistent, high dose steroid dependent
  asthma
• Prevention of infection and acute GVHD after bone
  marrow transplantation
• Prevention of acute humoral rejection after renal
  transplantation
• Pediatric autoimmune neuropsychiatric disorders
  associated with streptococcal infections
• Delayed pressure urticaria
• Treatment of acute humoral rejection after renal
  transplantation
• Autoimmune blistering skin diseases and
  manifestations of systemic diseases
• Chronic urticatria
• Autoimmune liver disease
• Acute myocarditis

63
Miscellaneous Use of Immune Globulin

• Unlikely to be Beneficial
• Prevention of spontaneous recurrent abortions
• Nonsteroid-dependent asthma
• Dilated cardiomyopathy
• Chronic fatigue syndrome
• Prevention of chronic GVHD after bone marrow
  transplantation
• Atopic dermatitis
• Autistic disorders

64
Safety and Efficacy of Immune Globulin

• Produced from paid plasmapheresis donors or
  plasma of whole blood donors
• Recommended large pool of donors to make product
  15,000 to 60,000
• Tested for
• Hepatitis B surface antigen
• HIV p24 antigen
• Antibodies to syphilis, HIV-1, HIV-2, Hepatitis C

65
Adverse Events of Immune Globulin Therapy

• 2002 Immune Deficiency Foundation survey of more
  than 1000 patients
• 44 reported reactions not related to the rate of
  infusion
• 34 of reactions occurred during the first
  infusion

• Most reactions were mild
• Back or abdominal aching or pain
• Nausea
• Rhinitis
• Asthma
• Chills
• Low grade fever
• Myalgias (muscle aches)
• Headaches

66
Managing Mild-Moderate Reactions

• Slow or stop infusion for 15-30 minutes
• Diphenhydramine, acetominophen, ibuprofen or
  aspirin
• Hydrocortisone 50-100 mg for adults, 5 mg/kg for
  children
• Intravenous hydration with normal saline
• To prevent reactions, pretreatment with any of
  the above may help

67
Severe Adverse Events with Immune Globulin

• Anaphylaxis and Anaphlylactoid reactions
• Hypotension, Steven-Johnson syndrome, myocardial
  infarction, thrombosis, cytopenia, hemolysis,
  stroke, seizure, loss of consciousness, acute
  respiratory distress syndrome, pulmonary edema,
  acute bronchospasm, transfusion associated lung
  injury, aseptic meningitis

68
Severe Adverse Events with Immune Globulin

• Events not related in time to infusion
• Acute renal failure
• More common in sucrose containing products
• Neurodegeneration
• Risk of transmitted infection
• Theoretical since more than 100 people infected
  with Hepatitis C in the 1990s

69
Practical Considerations in the Use of Immune
Globulin

• Definitely Beneficial
• Subcutaneous therapy to reduce systemic adverse
  events
• Maintain IgG troughs gt500 mg/dl to reduce
  infections
• Expert monitoring to manage adverse events of
  immune globulin therapy

70
Practical Considerations in the Use of Immune
Globulin

• Probably Beneficial
• Home based therapy for low risk patients can
  improve quality of life
• Use of low IgA content IVIG for IgA deficient
  patients with IgG anti-IgA antibodies
• Product changes might improve adverse event
  profiles
• Premedication can improve mild adverse events
• Matching particular IVIG products to patients to
  reduce adverse events
• Stopping or slowing infusion to help manage
  adverse events

71
Practical Considerations in the Use of Immune
Globulin

• Might Provide Benefit
• Subcutaneous therapy can improve quality of life
  for patients receiving IVIG
• Maintenance of IgG trough gt800 reduces infectious
  consequences
• Unlikely to be Beneficial
• Placement of indwelling catheters or ports for
  IVIG administration
• Making IVIG dosing and treatment decisions for
  antibody replacement therapy in PID solely upon
  IgG trough levels
• Routinely testing IgG trough levels more
  frequently than every 6 months

72
Acknowledgments References

• Bayer (immune system slides)
• Orange JS et al. J Allergy Clin Immunol
  117S525-53, 2006
• Siegel J. Pharmacotherapy 2578S-84S, 2005
• Good RA Lorenz E. Cancer 681415-21, 1991