hypersensitivity reactions to monoclonal antibodies aleena banerji, md assistant professor assistant...
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Hypersensitivity Reactions to Monoclonal Antibodies
Aleena Banerji, MDAssistant Professor
Assistant Training Program DirectorDivision of Rheumatology Allergy & Clinical Immunology
Harvard Medical SchoolMassachusetts General Hospital
Boston, MA
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Disclosures
I have no financial disclosures or conflicts of interest.
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Objectives
• Better understand clinical presentation of adverse reactions to monoclonal antibodies
• Discuss management of patients with adverse reactions to monoclonal antibodies
• Review the pathophysiology of adverse reactions to monoclonal antibodies
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Introduction• Rapid expansion of the use of biologics has
resulted in an increase in hypersensitivity reactions
• All biologics have the potential to induce immunogenicity– Degree of humanization– Pattern of glycosylation– Episodic administration– Concomitant medications
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Chimeric mAbs are Immunogenic
• Chimeric mAbs with human constant regions and murine variable regions contain non-self epitopes than can stimulate immune responses– Attempts to reduce the immunogenicity of chimeric
antibodies include total or partial removal of murine sequences
– Human mAbs are associated immune responses
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Background
• Biologics-related infusion reactions are often clinically consistent with type I hypersensitivity
• Antidrug antibodies are mostly represented by IgG isotype but a proportion of them may belong to IgE isotype
• Many immediate adverse reactions occur at re-exposure to the biologic after an interruption in therapy
Vultaggio et al., Curr Opin Allergy Clin Immunol 2011
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Commonly Used Biologicals
Hausmann et al., Med Clin N Am 2010
Fully Murine, Chimeric, Humanized, Fully Human
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Incidence of Infusion Reactions
Chung CH. Oncologist 2008
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Classification of HSRs to Biologics
Pichler et al., Curr Opin Allergy Clin Immunol 2011
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Mechanisms of Hypersensitivity ReactionsIgE and non-IgE mediated
Vultaggio et al., Curr Opin Allergy Clin Immunol 2011
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Mechanisms of Hypersensitivity ReactionsCytokine Release
Vultaggio et al., Curr Opin Allergy Clin Immunol 2011
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Evaluation of a Patient with HSR
Brennan et al., JACI 2009
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Decrease the Risk of a HSR
• Premedication– Steroids– Antihistamines
• Slowed infusion rates
• Desensitization
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Brennan et al., JACI 2009
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Management of Reactions during Desensitization
Brennan et al. JACI 2009
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Case: Hypersensitivity Reaction to Rituxan
• JM is a 72 year old male recently diagnosed with Non-Hodgkin’s Lymphoma, started on Rituxan therapy
• About one hour after starting his first infusion, he developed fever, chills and back pain
• Infusion was stopped and he received IV diphenhydramine and ranitidine– symptoms resolved within 35 minutes
• He refused rechallenge and presents today for your advice
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How do you evaluate JM’ssymptoms as a possible
hypersensitivity reaction to Rituxan?
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Rituxan Hypersensitivity
• Chimeric murine/human mAb against CD20 on
normal and malignant B lymphocytes
• Infusion reactions with fever, chills and rigor
reported in 5-10%
• Usually first dose within 30 minutes to 2 hours
– correlate with disease burden and decrease with
subsequent infusions
• Often resolve with slowing of the infusion
• Most reactions are not thought to be IgE-mediatedGrillo-Lopez et al., Semin Oncol 1999Dillman et al.,1999
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Mechanisms for Hypersensitivity to Rituxan
• Cytokine Release Syndrome: fever, chills, nausea, vomiting, hypotension, dyspnea– Increased serum TNF, IL-6
• Tumor Lysis Syndrome: renal insufficiency, hyperkalemia, hypocalcemia, hyperuricemia– Usually within 12-24 hours of infusion
• Pseudoallergic Reactions: urticaria, bronchospasm, hypotension, flushing
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Rituxan Skin Testing
• Performed at specific academic centers
• Little data on sensitivity and specificity with poor predictive value currently
• Reaction rate lower during desensitization in ST negative patients but reactions seen in both skin test positive and skin test negative patients
Epicutanous 10 mg/mL
Intradermal 0.1 mg/mL
Intradermal 1 mg/mL
Mechanism of hypersensitivity is unclear
Brennan et al. JACI 2009
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Management of Patients with HSR to Rituxan
• 23 patients underwent 105 successful desensitizations
Brennan et al. JACI 2009
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Infliximab Chimeric Monoclonal Antibody TNF
• Acute infusion reactions – Within 10 minutes to 4 hours– Can often continue with slowed infusions/premedication– With more severe reactions, desensitization has been
successful
• Delayed infusion reactions– Usually 5-7 days later– Arthralgias, fevers, malaise, urticaria, myalgias, “serum-
sickness” like
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Antibodies to Infliximab
• Antichimeric antibodies (ATIs) are produced in a substantial number of patients
• Positive correlation between ATIs and both acute and delayed infusion reactions along with reduced efficacy of treatment– Concomitant administration of methotrexate reduces
antibodies
• Not all patients with ATIs suffer from infusion reactions suggesting a role for other cofactors
• Shifting to another TNFantagonist generally tolerated
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Serum Anti-Chimeric Antibodies: Infliximab
Vultaggio et al. Allergy 2010
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Cetuximab
• Chimeric IgG1 monoclonal antibody EGFR
• HSRs reported in 1-22% of patients– Higher rates in certain regions
• HSR frequently reported within minutes of initial exposure
• Found to be related to antibodies specific for galactose--1,3-galactose present on Fab portion of cetuximab
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IgE Antibodies Binding to Cetuximab
Chung et al. NEJM 2008
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Cetuximab Structure and Glycosylation
Chung et al. NEJM 2008
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Management of HSR to Monoclonal AntibodiesSummary
• Approach will vary by drug and mechanism of hypersensitivity
– Discontinue drug and use reasonable alternative
– Slowed infusion
– Pre-medication regimen
– Induction of tolerance