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Hypersensitivity Reactions to Monoclonal Antibodies. Aleena Banerji, MD Assistant Professor Assistant Training Program Director Division of Rheumatology Allergy & Clinical Immunology Harvard Medical School Massachusetts General Hospital Boston, MA. Disclosures.

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Hypersensitivity Reactions to Monoclonal Antibodies

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Hypersensitivity reactions to monoclonal antibodies l.jpg

Hypersensitivity Reactions to Monoclonal Antibodies

Aleena Banerji, MD

Assistant Professor

Assistant Training Program Director

Division of Rheumatology Allergy & Clinical Immunology

Harvard Medical School

Massachusetts 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

Fully Murine, Chimeric, Humanized, Fully Human

Hausmann et al., Med Clin N Am 2010


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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’s

symptoms 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-mediated

Grillo-Lopez et al., Semin Oncol 1999

Dillman 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

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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InfliximabChimeric Monoclonal Antibody TNFa

  • 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 TNFa antagonist 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-a-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


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