Immunoglobulin therapy

Immunoglobulin
Therapy
• Topic Review
• July 10th, 2020
• Rapisa Nantanee, M.D.
• Pediatric Allergy and Immunology Unit
• King Chulalongkorn Memorial Hospital

Outline
• Structure of immunoglobulin
• History of immunoglobulin therapy
• Indication
• Mechanism
• Methods of delivery
• Adverse effects

Structure of immunoglobulin
• Immunoglobulins (Igs) are glycoproteins.
• Consists of two identical heavy chains (HCs) and two identical
light chains (LCs)
• Each HC or LC has two major domains referred to as the constant
region (C) and the variable region (V)
Fab fragments
• Able to bind antigen
• Variable domains of LCs and HCs combine
Fc fragment
• Bind to complement or Fc receptors (FcRs)
• Composed of the C-terminal portion of the HCs bound to each other
JT. Li, DF. Jelinek. Middleton 9th ed. Chapter 3.

IVIG
• Intravenous immunoglobulin (IVIG) preparations comprise the
pooled fraction of serum IgG from ~3,000–60,000 blood donors,
which is 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.
• Very much reflect the hierarchy present in the serum, consisting mainly
of IgG1 and IgG2 and containing much smaller amounts of the other
IgG subclasses.
I. Schwab, F. Nimmerjahn. Nat Rev Immunol 13, 176–189 (2013).

History of immunoglobulin therapy
‘‘Bloodserum’’ of rabbits
immunized with tetanus
toxin contained activity
against ‘‘tetanus
poison,’’ and such blood
serum transferred to
rabbits protected these
normal (naive) animals
against tetanus.
MM. Eibl. Immunol Allergy Clin N Am 28 (2008) 737–764.
1890
von Behring
and Kitasato
1910
Dr. A. Wolff-
Eisner
‘‘Curative Serum
Therapy and
Experimental
Therapy’’
handbook
1907
Cenci
Convalesce
nt human
sera for the
prevention
of measles
1930s
Antibodies
localized to the
immunoglobulin
(Ig)
compartment of
human serum.
1938
Karelitz
Prophylaxis
against
measles with
the globulin
fraction of
immune adult
serum
1952
Bruton
Successful
treatment of his
patient with X-
linked
agammaglobuli
nemia (XLA)
with
subcutaneous
gammaglobulin

Indication
EE. Perez, et al. J Allergy Clin Immunol 2017;139:S1-46.
Only licensed
indication of
SC
immunoglo-
bulin (SCIG)
None of the
original
immunoglobuli
n products that
were
specifically
licensed for
use are still
available in the
US market.

Indication: Primary immunodeficiency
• A framework of 6 distinct phenotypes of PI disease for which
immunoglobulin replacement is or may be indicated:
• (1) agammaglobulinemia due to absence of B cells
• (2) hypogammaglobulinemia with poor antibody function
• (3) normal immunoglobulins with poor antibody function
• (4) hypogammaglobulinemia with normal antibody function
• (5) isolated IgG subclass deficiency with recurrent infections
• (6) recurrent infections due to a complex immune mechanism related to a
genetically defined PI disease

1. Agammaglobulinemia due to the
absence of B cells
• The clearest indication of immunoglobulin replacement
• Evaluation of IVIG usage in patients lacking immunoglobulin has demonstrated a
clear benefit in terms of reducing both acute and chronic infections.
• In severe combined immunodeficiency (SCID), the T-cell defect is often
accompanied by an absence of B cells or B-cell function.
• Immunoglobulin replacement is warranted at diagnosis, post-transplantation period,
during gene therapy or enzyme replacement (for adenosine deaminase deficiency), until
B-cell function is restored.
• In some cases, B-cell function is never restored, and continual immunoglobulin
replacement remains necessary.

Early and prolonged intravenous immunoglobulin replacement therapy in
childhood agammaglobulinemia: A retrospective survey of 31 patients
P. Quartier, et al. J Pediatr 1999;134:589-96.
When IgG trough levels were maintained above 800 mg/dL, serious bacterial
illness and enteroviral meningoencephalitis were prevented.

JS. Orange, et al. Clinical Immunology (2010) 137, 21–30.
A recent meta-analysis of data from studies in
subjects with agammaglobulinemia described a
decreased risk for pneumonia with increasing trough
levels of up to 1000 mg/dL.
Trough IgG increased 121 mg/dL with
each additional 100 mg/kg in IVIG dose

2. Hypogammaglobulinemia with
impaired specific antibody production
• In patients with recurrent bacterial infections, reduced levels of serum
immunoglobulin, coupled with a lack of response to protein and/or polysaccharide
vaccine challenge (ie, in patients who cannot make IgG antibody against
diphtheria and tetanus toxoids and/or pneumococcal polysaccharide vaccine),
are a clear indication of immunoglobulin replacement.
• The prototype of this category is CVID.
• IVIG was associated with a reduced prevalence of infection compared with the
infection rate prior to IVIG treatment.
• Immunoglobulin replacement can decrease acute and chronic lung infections and
may prevent or slow the progression of their sequelae in antibody-deficiency
disorders, including XLA, CVID, and hyper-IgM.

Infection outcomes in patients with common variable immunodeficiency
disorders: Relationship to immunoglobulin therapy over 22 years
M. Lucas, et al. J Allergy Clin Immunol 2010;125:1354-60.
An annual infection
score of 0
Patients with
XLA also
displayed a
large range of
IgG levels to
maintain an
infection-free
state (8-13 g/L).
Doses of
replacement
ranged from 0.5
to 0.9 g/kg/mo.
Patients with a CVID
had a range of trough
IgG levels that
prevented
breakthrough bacterial
infections (5-17 g/L).
Doses of replacement
ranged from 0.2 to 1.2
g/kg/mo.
The findings from a recent prospective study in 90 patients with CVID and in a smaller group of patients
with XLA, followed for up to 22 years, support individualizing doses and trough levels to attain
infection-free outcomes rather than using a standardized dose in all patients by disease.

3. Normal levels of immunoglobulins with impaired specific-
antibody production (selective antibody deficiency)
• Patients with normal total IgG levels but impaired production of specific antibodies,
including those with isolated deficient responses to numerous polysaccharide antigens
following vaccination
• While antibiotic prophylaxis may represent a first-line intervention in these patients, the
severity of infection and/or the efficacy of antibiotic prophylaxis should be the driving force
behind any decision to provide immunoglobulin replacement therapy.
• Immunoglobulin replacement therapy should be provided when there is well-
documented severe polysaccharide non-responsiveness and evidence of recurrent
infections with a proven requirement for antibiotic therapy.
• Appropriate in, but not limited to, patients with difficult-to-manage recurrent otitis media at risk for
permanent hearing loss, bronchiectasis, recurrent infections necessitating IV antibiotics, failed
antibiotic prophylaxis, impaired quality of life due to recurrent infections despite antibiotic
prophylaxis, or multiple antibiotic hypersensitivities that interfere with treatment.

• The treatment may be stopped after a period of time (preferably in the
spring in temperate regions) and that the immune response will be
reevaluated at least 3-5 months after the discontinuation of
immunoglobulin.
• While some patients, usually children, show improved responses to antigen
challenge (typically with pneumococcal polysaccharide vaccine) after treatment with
immunoglobulin for 6-24 months and improve clinically, others require restarting the
immunoglobulin therapy because of a recurrence of infections.
• One or two cessations of therapy are likely to identify whether a patient’s defect in
antibody specificity was transient.
• Repeated multiple cessations of therapy to affect this determination are not useful
and can potentially harm the patient.
3. Normal levels of immunoglobulins with impaired specific-
antibody production (selective antibody deficiency)

normal-quality antibody response
• Transient hypogammaglobulinemia (THI)
• IgG levels normalize with age.
• Antibody function is initially partially impaired but ultimately typically intact.
• In select cases, treatment with replacement immunoglobulin may be
considered temporarily.
• Age-specific normal ranges of IgG vary, and 2.5% of healthy
individuals have ‘‘lower-than-normal’’ IgG (below the lower limit of the
95% confidence interval for age), which may not be clinically
significant, in the absence of recurrent infections.

• Isolated hypogammaglobulinemia (other than THI) can be a
feature of many immune function defects, and must be
differentiated from secondary causes.
• Increased loss of IgG, such as chylothorax, lymphangiectasia, or
protein-losing enteropathy
• Medication, especially corticosteroids, some seizure medications, and
certain biologics such as rituximab.

• A subset of patients also present with very low IgG and no history of
infection.
• Severe hypogammaglobulinemia should be considered a risk for
infection and should be managed accordingly.
• IgG level <150 mg/dL is widely accepted as severe hypogammaglobulinemia, for
which additional testing apart from verification of the low level is not required prior to
starting replacement therapy.
• Levels between 150 and 250 mg/dL are also considered severely low but warrant
consideration of additional testing for specific antibody against vaccines to assess
function, depending on the clinical history.

5. Normal immunoglobulin levels and normal
quality with deficient IgG subclass (IgG1, -2, -3)
• Isolated subclass deficiency is often asymptomatic, but a minority of
patients may have poor antibody responses to specific antigens and
recurrent infections.
• Prophylactic antibiotics and the treatment of other underlying
conditions, such as allergies or asthma, that may contribute to
recurrent sinopulmonary infections are the usual management.
• Immunoglobulin replacement for this use has been controversial.
• Immunoglobulin replacement should remain a therapeutic option in patients in
whom other ameliorative interventions have failed.

• The need for immunoglobulin therapy may arise as the only viable
option for therapy in PIs in which the mechanism underlying the
susceptibility to recurrent infection is not yet characterized, yet the
patient presents with recurrent infections and an otherwise normal or
near-normal immune function evaluation.
• Hyper-IgE syndrome who usually have normal serum IgG, IgM, and
IgA levels, but who may have defects in antibody responses.
6. Recurrent infections due to an unknown
immune mechanism

• Wiskott-Aldrich syndrome (WAS) is another immunodeficiency typically
characterized by normal total IgG, but with impaired specific-antibody
responses against both protein and polysaccharide antigens.
• Although it would be reasonable to consider patients with WAS as having selective
antibody deficiency, not all patients with WAS exhibit this phenotype.
• Owing to the diffuse immune effects in WAS, immunoglobulin therapy should
always be a consideration in this disease.
• The same considerations as for WAS apply to ataxia telangiectasia (AT)
as well as others of these types of combined immunodeficiencies,
including, but not limited to, deficiencies in STAT-3, nuclear factor-κB
essential modulator (NEMO), and STAT-1.
6. Recurrent infections due to an unknown
immune mechanism

Indication: Primary immunodeficiency
The indications of immunoglobulin therapy in various clinical presentations of immunodeficiency are likely to broaden
as the disorders are better understood, considering that a majority of PI diseases involve antibody deficiency.

Indication: Secondary immunodeficiency

Syndromic deficiencies with antibody defects
Patients with these
conditions should be
considered as
candidates for
immunoglobulin
therapy based on their
confirmed diagnosis
and clinical
presentation.
EE. Perez, et al. J
Allergy Clin Immunol
2017;139:S1-46.

Indication: Autoimmune disease
Rheumatic
disease

Mechanism of IVIG
• Replacement therapy
• Suppress the pathological immune responses that occur in
patients with autoimmunity

Mechanism of IVIG
• Intravenous IgG paradox
• IgG autoantibodies are also major contributors to the pathology observed in
several autoimmune diseases, for example, rheumatoid arthritis, systemic
lupus erythematosus (SLE), immunothrombocytopenia (ITP), autoimmune
haemolytic anaemia (AIHA) and chronic inflammatory demyelinating
polyneuropathy (CIDP).
• The same class of molecule that promotes pathology in a disease can also
be used as an anti-inflammatory treatment for the very same disease, as
exemplified by the successful treatment of ITP and CIDP with IVIG.

Pro-inflammatory activities of IgG
• IgG constant fragment (Fc fragment) is crucial for the pro-
inflammatory activities of IgG.
• It acts as an ‘adaptor’ to link the adaptive and innate immune systems.
• IgG can promote innate humoral immune responses through complement
component C1q-dependent activation of the classical complement pathway.
• It can activate innate immune cells by binding to Fcγ receptors (FcγRs). --
essential for the pro-inflammatory and cytotoxic effects of IgG autoantibodies
in autoimmune diseases.

The family of mouse and human FcγRs
Neutrophil
only
• Consists of several
activating receptors and
one inhibitory receptor in
both mice and humans
• These receptors are
broadly expressed by most
cells of the innate immune
system, including
basophils, eosinophils,
neutrophils, mast cells,
monocytes and
macrophages.
• Dendritic cells (DCs) and B
cells express select
members of the FcγR
family.

Mechanism of
IVIG activity
• Immunomodulation by the IgG variable
domain
• Immunomodulation by the Fc fragment of
IgG
• Involvement of FcRn in IVIG therapy
• IVIG and activating FcγRs
• Immunomodulation via FcγRIIB

Mechanism of IVIG activity:
F(ab′)2-dependent
Various self-reactive
IgG molecules are
present in IVIG
preparations, but
more work needs to
be done to elucidate
their contributions to
IVIG activity in vivo.
Anti-idiotypic antibodies: Antibodies that are
specific for the antigen-specific binding site of an
immunoglobulin or a T cell receptor and therefore
may compete with the antigen for binding

Immunomodulation by the Fc fragment of IgG

Involvement of FcRn in IVIG therapy
• One hallmark of IgG is its long serum half-life of 2–3 weeks, which is dependent
on the neonatal Fc receptor (FcRn).
• The function of FcRn is to bind serum IgG that has been endocytosed by
endothelial cells or myeloid cells under low pH conditions and recycle it back to
the cell surface.
• In the absence of FcRn, the half-life of IgG is reduced dramatically, which blocks the
initiation of tissue inflammation.
• One possible explanation for why large amounts of IVIG are needed for
therapeutic activity could be that the antibodies in IVIG preparations compete
with pathological autoantibodies for FcRn binding.

How glycosylation of
IgG affects IVIG activity

S. Jolles, et al. Clinical and Experimental Immunology, 179: 146–160. 2014.

NC. Patel. Pediatr Allergy Immunol. 2018;29:583–588.

IVIG
products

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Immunoglobulin therapy

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