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Chapter 24 Complement and Immunoglobulin Biology Leading to Clinical Translation 277

TABLE Early Systemic Adverse Events Associated With observed with IVIg treatment of neurologic diseases are related to a
24.3 Intravenous Immunoglobulin Infusion preexisting medical condition or the high doses required for treat-
Fever Rash or urticaria ment is not clear.
Chills Chest tightness Passive Immunization and Monoclonal
Sore throat Dyspnea Antibody Therapy
Face flush Wheezing
Tachycardia Low or high blood pressure Passive immunization in the broadest sense represents the transfer of
Palpitations Shock antibodies to a human recipient who is unable to produce the anti-
body due to the acuity of an infection, immunodeficiency, or immune
Lumbar pain Anxiety
tolerance to the target antigen. The use of plasma from patients who
Abdominal pain Nervousness have recovered from Ebola virus to treat those acutely ill with the
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Nausea Headache infection is an example of the simplest form of antibody transfer,
Vomiting Migraine where neither the antigenic epitope nor the sequence of the antibod-
ies are known, and there is no purification step. Indeed, the pathogen
Shaking Anaphylaxis need not be identified; it is only necessary that antibodies can clear
Fatigue Malaise the infection.
Myalgia Leukopenia With the use of intravenous immunoglobulin (described earlier)
to normalize IgG levels in patients with inherited immunodeficien-
cies (e.g., CVID or X-linked hypogammaglobulinemia) or chronic
lymphoproliferative disorders, the goal is to provide a wide range of
IgG immunoglobulins specific for antigens encountered by the
Premedication with steroids, aspirin, or other nonsteroidal antiin- general population, using a product purified from plasma donated by
flammatory drugs often decreases symptoms. Prophylaxis with pro- a large pool of healthy donors. Specialized IVIg products have also
pranolol can be effective for induced migraine. Aseptic meningitis is been developed that are enriched for antibodies that recognize specific
a rare early event, is observed 1 to 2 days postinfusion, is unrelated pathogens by prescreening donors. Examples include VariZIG (for
to infusion rate, and can be treated with intravenous steroids and varicella), Cytogam (CMV), HBIG (hepatitis B) as well as products
analgesics. 149,169 for rabies, botulinum toxin, and tetanus.
The frequency of reported adverse events varies considerably, Immunized animals once served as the major source of therapeutic
ranging from 10% to 85%. 149,159,170–172 There are many reasons for immunoglobulins; indeed, the modern medical era can be traced to
this high variability in reporting, including (1) differences in the late 1800s, when serum from horses immunized with diphtheria
product, 154,170,173 (2) infusion rate, (3) dose and frequency of dosing, toxin was first used therapeutically. The antigen used to immunize
(4) patient population, and (5) relative experience of patient and the animal need not be infectious: antivenom products can be used
physician. Both patients and physicians become steeled to the adverse to treat bites from coral snakes, pit vipers, black widow spiders, and
events, and because incidents are not life threatening and often scorpions. Some of these products are treated with proteolytic
respond to prophylaxis medication, they are ignored as “normal.” enzymes to produce Fab fragments, such as crotalidae polyvalent
Nonetheless, these events are common and affect health and quality immune FAB (Crofab). Digibind is another such Fab product,
of life of patients. 160,170 derived from sheep immunized with digoxin bound to human
albumin, as used to treat digoxin overdoses.
When the intended antigen is of human origin, there is the
Infectious Disease Transfer challenge that human plasma donors are likely to be tolerant to the
antigen. A notable exception is the Rh-D antigen, which, being
A few early preparations of IVIg transmitted hepatitis C virus. Manu- genetically polymorphic, is immunogenic to Rh-negative individuals,
facturers have added viral inactivation and partitioning steps, and and human-derived anti-Rh preparations can be used to prevent
current licensed products are safe with respect to HIV, hepatitis C sensitization during pregnancy and also as a treatment for immune
virus, hepatitis B virus, and other blood-borne pathogens (see Chapter thrombocytopenic purpura. However, apart from this special case,
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116). The industry has responded to the threat of prions with targeting human antigens generally requires a sensitized animal, a
process validation, 171,175 donor screening, donor testing, inventory prominent example being antithymocte globulin (ATG), which
management (look back), and plasma pool testing. induces lymphopenia as a treatment for aplastic anemia or as part of
an immunosuppressive regimen in organ transplantation.
Polyclonal antibodies can be advantageous in some cases (espe-
High-Dose Treatment–Related Adverse Events cially for ATG and antivenin) but the epitopes recognized and the
biologic activity may be variable between different lots of the product.
Intravenous immunoglobulin treatment for immune modulation of In retrospect, then, it is not surprising how Kohler and Milstein’s
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neurologic diseases requires doses of 1 to 2 kg/kg body weight or two technique for the generation of monoclonal antibodies quickly
to five times the dose recommended for replacement therapy. Adverse revolutionized medical diagnostics and almost all of biomedical
events with high-dose administration include those listed in Table research. Monoclonal antibodies as therapies came more slowly, and
24.3 and occasionally thromboembolic events, renal complications, there were initial concerns about the generation of “HAMA” (human
and anemia. 149,172,176–179 Thromboembolic events include deep venous antimouse antibodies). However, now there are modifications to
thrombosis, pulmonary embolism, myocardial infarction, and stroke. partially or fully replace mouse sequences with human sequences
Thromboembolic events and renal failure seem to be independent of (Fig. 24.10A). Furthermore, fully human antibodies can be generated
infusion rate. The cause of thromboembolic events is not known. using mice that are lacking mouse immunoglobulin genes and are
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180
Dalakas has suggested that increased serum viscosity plays a role. transgenic for the human sequences. Using mice with a germline
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Factor XIa has also been identified in IVIg preparations. Factor XIa knockout for the gene encoding the antigen of interest can enable
could directly lead to shortening of coagulation time and risk of the generation of antibodies that have been previously difficult
thrombosis. Renal complications are rare but result in high morbidity to obtain. 183,184 Four fully human monoclonal antibody products
and mortality. Whether IgG, contaminants, or excipients are respon- (ranibizumab, adalimumab, belimumab, and ramacirumab) now on
sible is not clear. Of the 88 renal adverse events reported to the FDA, the market were developed by an alternative method, phage display
90% were stabilized with sucrose. 149,169 Whether the adverse events (Fig. 24.10B). 185–189