Curr Allergy Asthma Rep (2013) 13:7884

DOI 10.1007/s11882-012-0316-x

ANAPHYLAXIS AND DRUG ALLERGY (P LIEBERMAN AND S SPECTOR, SECTION EDITORS)

Use of Omalizumab in the Treatment of Food Allergy

and Anaphylaxis
Jay A. Lieberman & Mirna Chehade

Published online: 11 October 2012

# Springer Science+Business Media New York 2012

Abstract Omalizumab is a humanized monoclonal anti-IgE

antibody that is currently FDA-approved for allergic asthma.
Given its mechanism of action, recent reports have suggested its
possible clinical use for food allergy and some forms of anaphylaxis. Omalizumab exerts its action by binding to circulating
IgE, reducing IgE receptor expression, and decreasing mediator
release from mast cells and basophils. Clinical trials using
omalizumab in patients with food allergy resulted in achieving
tolerance to higher amounts of the allergen in some patients.
When used as an adjunct therapy during immunotherapy trials
in patients with food allergy and anaphylaxis, omalizumab
allowed more rapid and higher doses of immunotherapy to be
given. Omalizumab has also been reported to be effective in a
few patients with idiopathic anaphylaxis and mast cell disorders. Large multi-center trials are needed to confirm the above
findings, and to identify subsets of patients that would benefit
the most from omalizumab.
Keywords Omalizumab . Anaphylaxis . Food allergy .
Treatment . Peanut allergy . Immunotherapy . IgE . AntiIgE . IgE-mediated food allergy . Immunotherapy .
Eosinophilic gastrointestinal diseases

J. A. Lieberman
Lebonheur Hospital, Division of Allergy and Immunology,
Department of Pediatrics, The University of Tennessee Health
Science Center,
Memphis, TN, USA
M. Chehade (*)
Mount Sinai Center for Eosinophilic Disorders, Jaffe Food Allergy
Institute, Mount Sinai School of Medicine,
One Gustave L. Levy Place, Box 1198, New York, NY 10029,
USA
e-mail: mirna.chehade@mssm.edu

Introduction
Anaphylaxis is a severe, life threatening, generalized or
systemic hypersensitivity reaction per the World Allergy
Organization [1]. Given this broad definition, it is clear that
anaphylaxis is not a single disease defined by a distinct
pathology and/or pathophysiology, but is rather a syndrome
defined by typical symptoms upon exposure to a known
trigger [2]. In fact, there is a wide array of etiologies that
can lead to a clinical definition of anaphylaxis, and not all of
these are immunologic [3]. Due to this dilemma, there does
not exist an all-encompassing therapy for anaphylaxis, rather management typically consists of avoidance of known
triggers and supportive treatment for any acute event.
Most cases of human anaphylaxis involve an immunoglobulin E (IgE)-mediated release of mediators from mast
cells and basophils [4]. These cases of classic hypersensitivity, such as that seen with food-induced anaphylaxis, first
require a sensitization phase in which antigen, through a
complex immunologic response, leads to the class switching
of B cells and the eventual production of antigen-specific
IgE. Circulating IgE molecules can then affix to the surface
of mast cells and basophils via the high affinity IgE receptor
(FcRI). Upon re-exposure to the antigen, IgE molecules
can bind to antigen, leading to cross-linking of IgE with
downstream cellular activation and eventual release of mast
cell and basophil mediators that are responsible for the
symptoms of allergy (Fig. 1a). Due to the central role that
IgE plays in these reactions, it becomes evident that an antiIgE molecule that does not lead to cross-linking of IgE on
mast cells and basophils may have therapeutic benefit in this
type of anaphylaxis. There is now both laboratory and
clinical data to suggest a possible role for the use of antiIgE therapy as an immune-modulating agent to decrease
anaphylactic events in these patients. In this article, we
review both in vitro and clinical data suggesting a role for

Curr Allergy Asthma Rep (2013) 13:7884

79

Fig. 1 a In allergic individuals, an allergen stimulates T cells to

produce IL-4 and IL-13. These cytokines stimulate B cells to produce
allergen-specific IgE. IgE molecules secreted into the circulation then
bind to high affinity receptors (FcRI) on the surface of mast cells and
basophils. Upon re-exposure to the allergen, cross-linking of IgE by

allergen results in release of various mediators causing allergy symptoms. b Omalizumab exerts its action by binding to free circulating
IgE, decreasing FcRI expression, and reducing mediator release from
mast cells and basophils

the commercially available anti-IgE, omalizumab, in the

treatment of anaphylaxis and food allergy.
Omalizumab is a recombinant humanized monoclonal
anti-IgE antibody that contains 5 % murine sequences
(needed for the IgE-binding portion) and 95 % human
residues [5]. It binds all IgE molecules (regardless of specificity) at an epitope in the C3 domain, which is the same
domain where IgE binds to the high affinity IgE receptor
FcRI [6]. Omalizumab binds to free IgE in the circulation
and not to receptor-bound IgE. Therefore, omalizumab does
not trigger degranulation, since it does not cross-link IgE
located on FcRI receptors of mast cells and basophils.

basic understanding of how omalizumab works. In the most

basic conceptual definition, omalizumab exerts its actions by
binding free IgE and thus severely reducing the amount of IgE
available on the surface of mast cells and basophils to bind
antigen. This idea is supported by data showing 99 % reduction
in free serum IgE levels in patients treated with omalizumab [7].
Interestingly, though, clinical outcomes of omalizumab therapy
do not necessarily correlate with reduction in serum levels of
free IgE [8]. This suggests that other immunomodulatory effects
of omalizumab may be clinically relevant (Fig. 1b).

Mechanism of Action of Omalizumab in Relation

to Anaphylaxis
Binding of Free Circulating Immunoglobulin E
To understand why omalizumab would have any utility in
treating anaphylaxis or food allergy, one must first review the

Reduction in Immunoglobulin Receptor Expression

IgE has the ability to regulate the cell surface expression of
its own high-affinity receptor (FcRI) [9]. Higher IgE levels
are associated with increased numbers of IgE receptors
expressed on mast cells and basophils. By decreasing free
IgE levels, omalizumab can break this positive feedback
loop, and has been shown to decrease FcRI expression on
many cell types, including mast cells (both cutaneous and
lung) and basophils [7, 1013]. This in turn decreases the

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potential of these cells to degranulate in response to the

allergen. In fact, in one study examining the effects of
omalizumab on nasal allergen challenge to ragweed in
ragweed-allergic subjects, the authors found a direct correlation between serum-free IgE levels and FcRI expression
on blood basophils, as well as a temporal relationship between nasal volume restriction blockade (clinical response)
and FcRI expression reduction, which occurred within 1
2 weeks on average [12]. There are also data showing that
omalizumab can reduce the FcRI expression on plasmacytoid and myeloid dendritic cells [14, 15]. In one study
examining cat-allergic subjects, this down-regulation of
FcRI on dendritic cells was associated with a decrease in
allergen-induced CD4+ T cell proliferation, and a decrease
in the cellular secretion of interleukin (IL)-5 and IL-10 by T
cells when co-cultured with allergen in the presence of
dendritic cells [15]. Unfortunately, this immunomodulatory
effect on T cells was not seen in a similar study of foodallergic patients [16].
Reduction in Mediator Release
In addition to decreasing FcRI expression on basophils and
mast cells, omalizumab can also lead to a functional change in
mast cells and basophils, by decreasing histamine release upon
exposure to antigen [7]. This finding has been extended more
recently in studies of patients being treated with omalizumab for
asthma, allergic rhinitis, and peanut allergy [1719]. One study
examining nasal allergic responses in cat-allergic patients suggested that the clinical effects correlated with reductions in
basophil histamine release (BHR), rather than mast cell histamine release (which occurred only later in therapy) [18].
Recent mechanistic studies in food allergy, however,
suggest that the effect of omalizumab may go beyond simply decreasing FcRI expression and BHR. Two recent
publications on omalizumab in peanut-allergic patients provide insight into possible mechanisms, and suggest why
omalizumab may not work for anaphylaxis in all patients
[19, 20]. In the first report, the authors found that a portion
of the patients had >80 % suppression of peanut-induced
BHR, but these patients did not tolerate any more peanut
post-therapy than those that did not show suppression of
BHR [19]. In fact, in those patients that did not have
suppression of peanut-induced BHR, higher peanut concentrations in vitro actually led to increased BHR post-therapy
as compared to baseline. To explain this discrepancy, the
authors examined these same patients in a second publication [20]. In this extended analysis, the authors propose that
basophil response to peanut allergen in vitro is dependent on
two factors: First, the antigen-specific/total IgE ratio, and
second, the extent in cellular responsiveness as measured by
basophil response to stimulation with a pan-crosslinking,
stimulating anti-IgE. Thus, if a patient has a high peanut

Curr Allergy Asthma Rep (2013) 13:7884

specific/total IgE ratio (>4 % used as a cutoff in this study)

and a high baseline basophil cell responsiveness to IgEmediated stimulation, this patients basophils are more likely to release histamine in vitro to lower amounts of peanut,
even after therapy with omalizumab. These findings may
lead to new insights in basophil biology, and may potentially provide a way to predict which food-allergic patients
would benefit from omalizumab therapy.

Clinical Studies of Omalizumab in Food Allergy

IgE-Mediated Food Allergy
Anti-IgE was first studied as a therapy for food allergy by
Leung and colleagues in 2003 [21]. In this randomized,
double-blind, placebo-controlled, dose-ranging study, the
authors examined the effect of another anti-IgE molecule
known as TNX-901 (Tanox Biosystems, Houston, TX, USA),
rather than omalizumab, in peanut allergic patients. Eighty-four
patients, 1260 years old, were randomized to receive monthly
subcutaneous injections of one of three doses of TNX-901 (150,
300, or 450 mg) or placebo for a total of 4 months. Within 2
4 weeks of the last dose, patients were challenged with increasing amounts of peanuts until a clinical reaction occurred. TNX901 increased the threshold dose of peanut eliciting a clinical
reaction in a dose-dependent manner, and this was statistically
significant at the highest dose (450 mg) when compared to
placebo. Patients who received 450 mg of TNX-901 had an
increase in the mean tolerable peanut dose from 178 mg peanut
flour (equivalent to half a peanut) pre-therapy to approximately
2,800 mg of peanut flour (equivalent to 9 peanuts) post-therapy,
an amount of tolerability likely to provide protection in the
event of an accidental ingestion of peanut in everyday life.
Some patients tolerated a dose as high as the equivalent of 20
peanuts at the post-therapy challenge. All three doses of the
drug decreased serum-free IgE levels by 88 % or greater from
baseline, and all doses were well tolerated with similar adverse
events as compared to placebo.
Further investigation using this antibody was discontinued
after an agreement among pharmaceutical companies that were
involved in the development of anti-IgE therapies. Subsequent
studies examined the use of omalizumab as a therapy for food
allergy. Recently, a phase II trial of omalizumab (Xolair; Genentech, South San Francisco, CA, USA) as a treatment for
peanut allergy was undertaken by Sampson and colleagues
[22]. This study was a multicenter, randomized, double-blind,
placebo-controlled trial that was designed to enroll 150 peanut
allergic subjects 675 years old. Prior to the study enrolling the
target number of subjects, 2 subjects suffered anaphylaxis at
study entry, during the double-blind peanut challenge performed prior to receiving any study drug. Due to the severity
of these reactions, the study was terminated early. As a result,

Curr Allergy Asthma Rep (2013) 13:7884

only 14 subjects completed the study (9 in the active arm and 5

in the placebo arm). The limited data resulting from this study
suggested that subjects who received omalizumab were able to
tolerate more peanut at the post-24 weeks therapy peanut challenge than those subjects receiving placebo (P00.054). In
addition, 44 % of the omalizumab-treated subjects were able
to tolerate the goal dose of 1 g of peanut protein after 24 weeks
of therapy as compared to only 1 subject in the placebo-treated
arm. As with the previous study, the clinical benefit did not
seem to correlate with reductions in serum-free IgE levels, as all
subjects in the omalizumab group achieved adequate reductions
in serum IgE levels. This again indicates that serum-free IgE
levels could not be followed as a clinical marker of drug
responsiveness, and that the mechanism of action of omalizumab goes beyond simple reduction of IgE antibody levels.
More recently, Savage and colleagues reported results from a
single-center, open-label trial of omalizumab in adult peanutallergic subjects [19]. The authors enrolled 14 subjects and
administered omalizumab over 6 months per package insert
dosing guidelines (150750 mg every 24 weeks). All subjects
had a baseline peanut challenge. They were then challenged a
second time at some point between weeks 2 and 8, whenever
their peanut allergen-induced BHR dropped to <20 % in response to omalizumab, and a third time at week 24, the study
conclusion point. Subjects treated with omalizumab could tolerate more peanut after treatment as compared to baseline
(median of 80 mg at baseline peanut challenge; median of
6,500 mg at the initial post-therapy peanut challenge, P0
0.002; and median of 5,080 mg at the final peanut challenge,
P00.005). This study was not a placebo-controlled trial, but
these data suggest that clinical benefits of omalizumab may
occur early on in therapy, following administration of a few
doses of omalizumab.
Given the obstacles and results of the preceding studies, it
is unclear if omalizumab will ever have a role as a single,
therapeutic agent for IgE-mediated food allergy. However,
with the recent surge in studies examining immunotherapy
protocols for food allergies, and given the ability of omalizumab to reduce allergic reactions to food allergen challenges,
omalizumab may have an adjunct role in the treatment of food
allergies. Studies examining oral immunotherapy (OIT) without omalizumab report high levels of oral and gastrointestinal
side effects, which can lead to therapy cessation by some
subjects [23, 24]. Thus, there may be a role for omalizumab
to decrease these side effects, and so allow more subjects to
tolerate desensitization protocols. In a pilot study, Nadeau and
colleagues examined the use of omalizumab as an adjuvant to
a rush protocol for milk OIT [25]. The authors enrolled 11
milk-allergic subjects, 717 years old, and treated them with
omalizumab per package insert dosing guidelines (150
300 mg every 24 weeks) for 16 weeks in an open-label
protocol. Nine weeks after the start of omalizumab treatment,
rush desensitization to milk was performed in two phases,

81

increasing the dose of milk from 0.1 mg to 1,000 mg over

1 day, and then to 2,000 mg over 711 weeks. Throughout the
dose-escalation period, subjects remained on omalizumab.
Nine subjects tolerated the rush desensitization protocol
reaching a target dose of 1,000 mg. Following discontinuation
of omalizumab, subjects continued to ingest milk daily at
home. The 9 patients who eventually reached the daily target
OIT dose of 2,000 mg passed a double-blind and open milk
challenge at week 24 using 4,0008,000 mg of milk. They
continued milk ingestion of essentially normal amounts of
milk, consisting of more than 8,000 mg (240 ml) per day.
With these promising results, there are currently ongoing trials
examining the use of omalizumab with desensitization protocols to various foods at various centers (clinicaltrials.gov
identifiers: NCT01157117, NCT01290913, NCT00932282).
Eosinophilic Gastrointestinal Diseases (EGID)
The above clinical studies evaluated the use of omalizumab
in IgE-mediated food allergies. EGID and eosinophilic
esophagitis (EoE) do not share this same pathophysiology
as IgE-mediated food allergies. These diseases are driven by
multiple food allergens that exert their effect by a mix of
IgE- and non-IgE-(cell)-mediated mechanisms. A T-helper
type 2 allergic phenotype is characteristic of these diseases,
leading to tissue eosinophilia, esophageal in the case of
EoE, and gastric and/or duodenal in patients with EGID.
Data from studies of omalizumab in asthmatic patients and
its effect on skin mast cell numbers in allergic patients suggest
that omalizumab can decrease tissue eosinophilic infiltration
[10, 11]. Based on these findings, an open-label, pilot study
on the effect of omalizumab on patients with EGID was conducted [26]. In this report, the authors enrolled 9 patients with
EGID to receive omalizumab 375 mg every 2 weeks for
16 weeks. At the doses used, the authors achieved significant
decrease in serum-free IgE levels and in basophil and dendritic
cell FcRI expression. Patients symptoms improved when
evaluated both halfway through the study and at the end of
the study duration, but this improvement did not correlate with
changes in blood or tissue eosinophilia. The absolute peripheral
eosinophil count was reduced in the group, but the decrease was
significant only at week 16, with a median decrease of 34 %.
Gastric and duodenal tissue eosinophils decreased in number
while on therapy, but this decrease did not reach statistical
significance. In the subset of patients with EGID who had
concomitant esophageal eosinophilia, esophageal eosinophil
numbers were unchanged (instead, an increasing trend was
seen, but it was not statistically significant). The results, however, suggest a possible role for omalizumab, likely in combination with other therapies, as a therapy for EGID.
As for the use of omalizumab for eosinophilic esophagitis
(EoE), published data are thus far limited to a case report of
two severely atopic patients with EoE who had symptom

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improvement with omalizumab, given as 300 mg twice a month

in the adult patient and once a month in the child [27]. In this
report, both patients had improvement of their food-induced
cutaneous, respiratory, and digestive symptoms. Resolution of
symptoms related to esophageal dysfunction occurred in one of
the patients. No improvement in esophageal endoscopic appearance or esophageal eosinophilia on histological assessment was
seen. Nonetheless, given the potential role of omalizumab in
treating this disease, clinical trials to examine the use of omalizumab in EoE are in progress (clinicaltrials.gov identifiers:
NCT00123630, NCT01040598).

Use of Omalizumab to Decrease Anaphylaxis Associated

with Immunotherapy
The utility of combining omalizumab with allergen specific immunotherapy (IT) was first reported in pollen
allergic patients in 2002 [28]. This study demonstrated
that omalizumab, dosed per package insert, provided an
increase in efficacy with regards to symptom control
beyond IT alone and suggested that the combination
was safe; but did not examine its role in decreasing
systemic reactions to IT. Since that initial study, several
well-designed trials have examined whether omalizumab
can decrease systemic reactions associated with IT, specifically examining IT regimens associated with high
rates of anaphylaxis, such as rush IT protocols and
venom IT. In 2006, Casale and colleagues reported
results from a multicenter study examining omalizumab
given in conjunction with ragweed rush IT [29]. The
authors randomized 159 patients to receive pretreatment
with either omalizumab, dosed per package insert, or
placebo, prior to receiving rush IT versus placebo. They
found that the percentage of patients with serious adverse events in the IT + omalizumab group was 2.6 %
as compared to 15.0 % in those receiving IT + placebo.
Thus, omalizumab led to a 5-fold reduction in the risk
of anaphylaxis caused by rush IT in ragweed-sensitive
allergic rhinitis patients, when compared to placebo.
More recently, investigators examined the effect of omalizumab on side effects of a cluster IT regimen to cat, dog,
and/or house dust mite [30]. Unlike in the previous study,
the investigators here specifically selected asthmatics (moderate, persistent, or more severe) who had symptoms despite
use of inhaled corticosteroids, and would thus qualify for
omalizumab based on asthma alone. A total of 275 subjects
were randomized to receive either omalizumab, dosed per
package insert, or placebo for 16 weeks. At week 13, both
groups then received a cluster IT regimen based on their
sensitizations that lasted for 4 weeks, following which they
remained on maintenance IT for 7 weeks. Findings revealed
that 13.5 % of those in the omalizumab group suffered a

Curr Allergy Asthma Rep (2013) 13:7884

systemic allergic reaction, while 26.2 % of those subjects in

the placebo group suffered a systemic allergic reaction
(P00.006). In addition, subjects in the omalizumab group
required a total of 9 doses of epinephrine at any time during
the study, while those in the placebo group required a total
of 22 doses of epinephrine. This study showed that omalizumab was associated with fewer systemic reactions to
specific IT in asthmatics, and allowed more subjects to reach
a target IT maintenance dose.
Omalizumab has also been reported to decrease adverse
events associated with venom IT. However, data for this
come from various case studies [31, 32], rather than from
a clinical trial.
Results from all the above studies show that omalizumab
use may permit more rapid and higher doses of allergen
immunotherapy to be given more safely and with greater
efficacy to patients with allergic diseases.

Use of Omalizumab to Decrease Anaphylaxis Events

in Other Conditions
Idiopathic Anaphylaxis
In cases of anaphylaxis where triggers cannot be identified,
patients and clinicians can become quite frustrated, as they
are not left with the option of avoidance of triggers. Because
there is no ideal prophylactic therapy currently available,
clinicians are often trying to find alternative forms of therapy for these patients. While there is no well-designed trial
of omalizumab for idiopathic anaphylaxis, there are case
reports suggesting a benefit of omalizumab in decreasing
anaphylactic events for these patients [3335]. Clearly, these
cases do not prove causation or efficacy of this therapy, but
they may provide clinicians with a therapeutic option in
patients with recurrent, idiopathic anaphylaxis.
Mast Cell Diseases
As with idiopathic anaphylaxis, there is no formal trial
examining the use of omalizumab in systemic mastocytosis
or mast cell activation syndrome. Rather, data suggesting a
role for its use come from case reports from around the
world [3641]. These case reports suggest that omalizumab
may decrease anaphylactic events in these patients.
Other Forms of Anaphylaxis
Finally, there are also case reports suggesting the efficacy of omalizumab in exercise-induced anaphylaxis
and for fire ant-induced anaphylaxis as a monotherapy
in patients that cannot tolerate or fail immunotherapy
[42, 43].

Curr Allergy Asthma Rep (2013) 13:7884

Omalizumab-Associated Anaphylaxis
This manuscript is meant to review the use of omalizumab as a
treatment for food allergies and anaphylaxis, but a discussion
of this topic would not be complete without a brief evaluation
of data regarding omalizumab as also a cause for anaphylaxis.
Due to reports of anaphylaxis to omalizumab, a joint task
force of the American Academy of Allergy, Asthma & Immunology and the American College of Allergy, Asthma &
Immunology was convened in 2007 to review all available
data on anaphylaxis associated with omalizumab infusions
[44]. The task force reported that anaphylaxis occurred in
approximately 0.09 % of 39,510 patients receiving omalizumab injections between the years of 2003 and 2006. Sixty-one
percent of these reactions occurred within the first 2 h with the
first 3 injections and another 14 % occurred within 0.5 h after
the fourth or later injection. Based on these findings, the task
force established guidelines when treating patients with omalizumab, which include prescribing an epinephrine autoinjector to all patients receiving omalizumab and observing all
patients for 2 h after the first 3 injections and for 30 min after
all other injections; although they do suggest that this can be
modified based on the clinicians judgment after discussion
with the patient. This same task force continued to meet and
assess ongoing data and published a follow-up report in 2011,
which reviewed all reported cases from 2006 to 2009 [45]. In
this report, they concluded that the timing of reactions was
consistent in the follow-up data and re-affirmed that the guidelines were adequate. To assess if patients are at risk of an
allergic reaction to omalizumab, the task force found that prick
skin testing to omalizumab using various dilutions, and intradermal testing with an omalizumab concentration of
1:100,000 (containing 1.2 mcg of omalizumab per ml) can
be safely performed without producing an irritant response.

Conclusions
Omalizumab is a humanized monoclonal anti-IgE antibody
that is currently FDA-approved for allergic asthma. Given
its mechanism of action, recent studies and case reports have
suggested its possible clinical use for other IgE-associated
conditions, such as food allergy and some forms of anaphylaxis. Currently, there are data to suggest that, as a monotherapy, omalizumab may allow food-allergic patients to
tolerate higher amounts of the allergic food before reacting,
and, thus, may provide protection to accidental ingestions.
This protection does not extend to all patients, however, and
a better understanding of which patients respond to therapy
is an active area of investigation. Studies have also shown
that omalizumab, when added to various forms of IT, e.g.,
rush forms of milk oral IT and ragweed IT, it can decrease
systemic allergic reactions during the build-up IT phase and

83

thus allow more patients to successfully tolerate and complete this therapy. Finally, case reports from around the
world have shown anecdotal evidence of the utility of omalizumab as monotherapy in idiopathic anaphylaxis and mast
cell disorders. Thus, with ongoing and future clinical trials,
clinicians may have an additional therapeutic option for
patients with food allergy and anaphylaxis.

Disclosure No potential conflicts of interest relevant to this article

were reported.

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