SIAAIC Toscana 2014 Nuove opportunità diagnostiche per la gestione clinica delle reazioni avverse a farmaci biologici Alessandra Vultaggio AOU Careggi (Florence, Italy) Department of Biomedicine Immunoallergology Unit vultaggioa@aou-careggi.toscana.it
Adverse Events Adverse Events (AE): Any untoward medical occurrence associated with the use of a drug, Infusion whether or not drug related Reactions Infusion Reactions (IR): Any AE caused by the drug Hyper sensitivity Hypersensitivity Reactions: reactions Antibody- or cellular-mediated IR Biological agents-related hypersensitivity reaction: a SUBMERGED and EMERGENT problem !!! (2014, in press)
Clinical management of hypersensitivity reactions Patients with Patients with no previous reactions previous reactions Definition of pathogenic Identify patients at risk mechanisms Prevention of further or first time reactions
Infusion reactions to biologicals : extension and timing of onset LOCAL LOCAL SYSTEMIC SYSTEMIC IMMEDIATE DELAYED IMMEDIATE DELAYED OCCUR DURING OR OCCUR FROM 1 HOUR TO WITHIN 1 HOUR AFTER 14 DAYS AFTER INFUSION INFUSION OCCUR WITHIN A FEW OCCUR AT LEAST 1 DAY MINUTES AFTER AFTER INJECTION INJECTION Pichler WJ, Allergy 2006 Maggi E et al, Exp Rev Clin Immunol 2011
Pathogenic mechanisms of reactions to biological agents (BA) IMMEDIATE systemic REACTIONS IMMEDIATE systemic REACTIONS • Non antibody-mediated adverse reactions Complement-mediated Cytokine release syndrome (CRS) • Antibody-mediated adverse reactions IgE-mediated Antibody-mediated = Hypersensitivity Non IgE-mediated Vultaggio A et al, Curr Opin Allergy Clin Immunol 2012
BA-induced cytokine release syndrome FcγRI Mø Biological agent C Y T O Flu-like Flu-like K reactions reactions Activation I N C’-mediated lysis Anaphylaxis-like E reactions MAC Target D i r e cell c t a p o R p t o s i s ADCC-mediated lysis E Cytokine storm L E NK cell A S E Vultaggio A, Maggi E, Matucci A Curr Opin Allergy Clin Immunol 2011
Overlap between CRS and HYPERSENSITIVITY Antibody-mediated CRS Hypersensitivity Fever Headache Angioedema Rash Myalgias Dizziness Hypotension Diarrhea Bronchospasm Dyspnea MOF Pruritus Tachycardia Nausea Different mechanisms Different approaches to avoid future reactions
Which tools are available for the clinician to manage the infusion reactions? – In vitro tests for ADA – In vivo tests to detection and • Skin testing for IgE- Isotyping mediated HRs • Non isotype-specific ADA assay • IgE Isotyping T cell assays: their role to be defined
Detection of ADAs: current methods Each of these methods has benefits and limitations !! Immunochemical methods Binding assays (ELISAs, RIA, elettrochemiluminesce) Biophysical methods Surface plasmon resonance • ELISA bridging format is the Bioassays most used test
Comparison of different tecniques to monitor anti-drug antibdies • IFX-treated patients • IFX-treated patients • BID patients (CD) • BID patients (CD) • ELISA, RIA, EIA, RGA • ELISA, RIA, EIA, RGA Performances of assays are comparable. However, anti-IFX Ab titers show systematic differences, and in individual patients, only the same assay should be used. Problems may arise when different assays are used to manage therapies in the same patient. (Vande Casteele N et al, Aliment Pharmacol Ther 2012 )
Immediate systemic reactions to IFX are associated with ADA formation 100 0 17,9 17.6 80 % of patients 61,1 75 60 93,2 100 40 82,1 82.4 20 38,9 25 6,8 0 PARTIALLY NON TOTALLY NON REACTIVE/NON RESPONDER REACTIVE RESPONDER RESPONDER RESPONDER (n=103) (n=34) (n=28) (n=36) (n=9) ATI - 96 (93.2%) 21 (75%) 22 (61.1%) 6 (17.6%) 0 (0%) ATI + 7 (6.8%) 7 (25%) 14(38.9%) 28 (82.4%) 9 (100%) Vultaggio A, Matucci A et al, Allergy 2010 and unpublished data
IgG ADAs Isotype Antibodies towards biotherapeutics are mainly of the IgG isotype (IgG1 subclass) Monitoring patients treated with anti-TNFa biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies Svenson M et al, Rheumatology 2007
ADR towards biologics: a model IgG pathway of anaphylaxis in mice High amount of High amount of antibody antigen Maggi E, Vultaggio A, Matucci A Exp Rev Clin Immunol 2011
IgE ADA isotype IgE-mediated reactions have been described towards several BAs Drug In vivo In vitro Ref Georgitis, 1991 Muromonab No Yes Chung, 2008 Cetuximab No Yes Stubenrauch, 2010 Tocilizumab No Yes Baudouin , 2003 Basiliximab No Yes Price, 2007 Omalizumab Yes No Bavbek, 2011 Etanercept Yes No Paltiel, 2008 Adalimumab Yes No Brennan , 2009 Rituximab Yes No MunozCano, 2010 Natalizumab Yes Yes Vultaggio, 2010 Infliximab Yes Yes Vultaggio, 2012 Rituximab Yes Yes Vultaggio A et al, Allergy 2010 Maggi E, Vultaggio A, Matucci A Matucci A et al, Clin Exp Allergy 2013 Exp Rev Clin Immunol 2011
IgE-mediated IFX-related events: Update of our experience Infliximab-specific IgE ADAs ADR+ patients n=34 ATI+ patients n=28 (82.4%) IgE+ patients n=7 (25%) Vultaggio A et al, Allergy 2010 Matucci A et al, Clin Exp Allergy 2013 And Unpublished data
The Relevance of IgE Isotyping: Why not “Just do it”? the analysis of specific IgE anti-drug antibodies the analysis of specific IgE anti-drug antibodies is challenging is challenging • The level of circulating specific IgE antibodies is usually low (1 ng/ml) • The timeframe in which sIgE is detectable in serum is quite short 1 Non-isotype-specific ADA IgE ADA 0,8 • Assays are sensitive to: 0,6 OD – Circulating drug 0,4 – Antidrug antibodies 0,2 of other isotypes 0 +7 +14 +21 +28 BaselineDay of reaction Days post reaction
Serum detection of IgE anti-drug antibodies: Type of assay Drug In vitro Ref Georgitis, 1991 Muromonab Yes, ELISA Chung, 2008 Cetuximab Yes, ImmunoCAP Stubenrauch, 2010 Tocilizumab Yes, ImmunoCAP Baudouin , 2003 Basiliximab Yes, ELISA MunozCano, 2010 Natalizumab Yes, ImmunoCAP Vultaggio, 2010, Matucci 2013 Infliximab Yes, ImmunoCAP Vultaggio, 2012 Rituximab Yes, ImmunoCAP
Why to measure BA-specific IgE?
Highest incidence of anti-drug IgE in severe reactions 1. IgE-mediated reactions have peculiar clinical characteristics 1. IgE-mediated reactions have peculiar clinical characteristics 100 80 % of IgE+ patients 60 40 20 0 p<0.02 Hypereactivity Tolerant Severe Hypereacitivy Mariotte D et al, mAbs 2011 Matucci A al, Clin Exp Allergy 2013
Timing of the development of reactions 2. IgE-mediated reactions usually occur earlier and 2. IgE-mediated reactions usually occur earlier and more frequently after a period of interrruption more frequently after a period of interrruption ATI+ IgE+ ATI+ IgE- N° of patients ATI- (N° of infusions) ATI+ IgE+ ATI+ IgE- 1° Cycle 2/7 (28.6%) 14/16 (87.5%) Re-exposure 5/7 (71.4%) 2/16 (12.5%) p<0.02 Matucci A et al, Clin Exp Allergy 2013
Can diagnostic tools predict BA-induced infusion reactions?
A role for ADA assays in the identification of patients at risk (A.Vultaggio, A.Matucci et al Allergy 2010) 1 Non-isotype-specific ATI IgE ATI 0,8 Hypersensitivity risk 0,6 can be detected prior to OD clinical symptoms !! 0,4 0,2 0 +7 +14 +21 +28 Baseline Day of reaction Days post reaction
IgE-mediated reactions at first exposure The Cetuximab case The Cetuximab case Chung CH et al, NEJM 2008 Sensitization First exposure to to Gal- 1-3Gal Cetuximab Cetuximab (SP2) M e a t Murine part A IgE l IgE l e r g y G 1-3G G 1-3G Hypersensitivity Reaction Gal- 1-3-Gal Injection Gal- 1-3-Gal (Matucci A. et al. EAACI 2014
Anti-cetuximab IgE as a valuable screening test
5 out of 6 resulted IFX POSITIVE 6 patients with meat allergy but IFX-naive IgE anti-IFX antibodies probably pre- exist Delayed anaphylaxis to the treatment to meat Are they specific for glycans? Previous history of tick bites What is their clinical significance? Do 2 different pathway of sensitization toward IFX exist?
Serum detection of IgE anti-drug antibodies: Clinical studies Culprit Method Pts Controls Sens Spec PPV NPV Author drugs Pre- existing 78 Mariotte D cross- unreactive ELISA 14 CTX 71.4 82.1 33.3 98.5 (2011) reactive 117 HD ADA 20 New untreated; developed Matucci A non cross- CAP 30 15 INF 26 90 26 89 (2013) reactive unreactive; ADA 15 LOR
ADA-positive but IgE-negative reactive patients: why? TRUE IgE-NEGATIVE FALSE IgE-NEGATIVE Interference by other antibodies in the assay Other isotypes of ADAs involved in the induction of OR hypersensitivity reactions Very low circulating IgE levels (bound on cells)
Can skin testing help clinicians in the allergological work-up for IgE-mediated hypersensitivity reactions ?
Skin testing for BA In vivo tests are not currently standardized and approved for BA • Limited data in literature • Positive skin testing has been reported mainly in patients with HRs caused by: – antiTNF agents – Rituximab – Trastuzumab • A Few studies (small case series) report results of skin testing confirmed by in vitro assay – Infliximab – Rituximab – Natalizumab
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