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16. Dr. Carlo Pini - Superior Institute of Health (Italy)
 

16. Dr. Carlo Pini - Superior Institute of Health (Italy)

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“Immunogenicity as a key issue for biotechnology-derived products” ...

“Immunogenicity as a key issue for biotechnology-derived products”


Explains the concept of immunogenicity in biotherapeutics and gives an overview of relevant EU guidelines and norms

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    16. Dr. Carlo Pini - Superior Institute of Health (Italy) 16. Dr. Carlo Pini - Superior Institute of Health (Italy) Presentation Transcript

    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 11Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 11Immunogenicity as a keyissue for biotechnology-derived products.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 22Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 22Carlo Pini(carlo.pini@iss.it)DirectorNational Center for Immunobiologicals Research andEvaluation - CRIVIBIstituto Superiore di SanitàRomaItalian Delegate - Biologics Working Party (CHMP/BWP)EMA - London
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 33Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 33Disclaimer• The content of the following presentation representsthe speaker’s view and does not reflect any officialpoint of view.• According to the EMA policy (0044 MA/513078/2010)– No direct conflict of interest– One indirect conflict of interest
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 44Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 44Biologicals/biotechnologicals products• Biologicals/biotechnologicals products arecomplex macromolecules which cannot be fullycharacterised from the analytical point of view butwhose quality attribute are also largely definedby the manufacturing process.• They may be:– copies of naturally occurring molecules normallypresent in the human body such as interferons, growthfactors (G-CSF, erithropoietin ) antibodies, etc.– “foreign molecules” which have been designed tointerfere with a certain pathogenic mechanism.– Molecules which have been intentionally designed tobe immunogenic (recombinant vaccines).Immunogenicity is therefore a positive characteristicof the product.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 55Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 55Immunogenicity• With the exception of vaccines, immunogenicity is anegative unwanted property of a given molecule, and anumber of attempts have been made to design a recombinantmolecule to reduce/abolish this characteristic.• The predictive value of non-clinical studies for evaluation ofimmunogenicity of a biological medicinal product inhumans is low due to inevitable immunogenicity of humanproteins in animals.• Differences between neutralising vs non-neutralisingantibodies.• In the clinical setting, careful planning of immunogenicityevaluation should include data systematically collected froma sufficient number of patients.• Immunogenicity issues should be further addressed in theRisk Management Plan.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 66Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 66Immunogenicity• The consequences of an immune reaction to a therapeutic protein rangefrom transient appearance of antibodies without any clinicalsignificance to severe life-threatening condition.• The immunogenicity of therapeutic proteins. can be considered to bepatient-, disease- or product-related• data on possible unwanted immune reactions to therapeutic proteins arerequired before marketing authorisation, problems may still beencountered in the post-authorisation period.• Depending on the immunogenic potential of the therapeutic protein andthe rarity of the disease, the extent of immunogenicity data beforeapproval might be limited• Further systematic immunogenicity testing might become necessaryafter marketing authorization, and may be included in the riskmanagement plan.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 77Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 77Immunogenicity• A lot of experience has been gained since thevery first recombinant product (murinemonoclonal antibody – Muromomab CD3 –middle 1980s) was authorized.• As a consequence, several technical approacheshave been introduced to manufacture less andless immunogenic products• For example, murine MoAb from ascites havebeen replaced by fully humanized MoAbs wherethe only “foreign” structure is represented by afew aas defining the binding region.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 88Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 88Immunogenicity• The progress of the scientific knowledge in the field has suggestedin the recent past that the immunogenicity issue should be largelytreated in a CHMP Guideline (CHMP/BMWP/14327/06).• The Guideline came into effect in April 2008• A number of important aspects have been covered in the document• The scope of the Guideline is not restricted to recombiant productsbut it applies to biologicals in general, when feasible.• Very important point, this guideline should be considered togetherwith the relevant guidelines on Biosimilar products and onComparability (quality, non clinical and clinical parts).– Impact of changes in the manufacturing process on immunogeniciy– Immunogenicity of the biosimilar product• Therefore evaluation of immunogenicity should be amultidisciplinary task, encompassing joint efforts of quality, non-clinical and clinical experts.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 99Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 99Immunogenicity (CHMP/BMWP/14327/06)• Guideline on immunogenicity assessment of Therapeutic proteins– Immunogenicity guideline: general section• Basic concepts, immunogenicity and humanisation, molecular size, percentageof murine parts, etc.• Patients and disease related risk factor.• In the comparability exercise (post changes products and biosimilars, theimmunogenicity in non clinical model may provide useful information.The antibody you get may be irrelevant or may neutralise the whole activity ofthe drug. Distinction between neutralising and non-neutralising antibodies.PK influencing antibodies not easily determined and distinguished from theneutralising antibody.• Difference between infusion reaction and anafilactic reaction which shouldprevent the patient to get treated.• Risk management and standardised measurements methods.– Immunogenicity guideline: Annex I• Unwanted immunogenicity and various types of antibodies and differentantibodies require different methods.• It is impossible to predict a number of factors with antibodies and studiesare required.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1010Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1010General section• Factors that may influence the development of animmune response against a therapeutic protein– Patient- and disease-related factors• Genetic factors modulating the immune response• Disease-related factors and age• Concomitant treatment• Duration, route of administration, treatment modalities• Previous exposure to similar or related proteins– Product related risk factors of immunogenicity• Protein structure• Formulation• Aggregates and impurities
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1111Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1111General section• Non-clinical assessment of immunogenicity and itsconsequences– Therapeutic proteins show species differences in most cases. Thus,human proteins will be recognised as foreign proteins by animals.– Measurement of antibodies in non-clinical studies are howeverrequested as part of repeated dose toxicity studies (see ICH S6)– the comparison of the antibody response to the reference product inan animal model may be part of the comparability exercise both forsimilar biological medicinal products and for changes inmanufacturing processes– An immune response to a therapeutic protein representing acounterpart to an endogenous protein may result in cross-reactivity,directed to the endogenous protein in cases where endogenousprotein is still produced.– Both humoral and cellular immune responses (where relevant)should be considered.– Animal homologous models useful
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1212Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1212General section• Assays for detecting and measuring immuneresponses in humans.– Assay strategy– Antibody assay• Screening• Confirmation• Specificity• Neutralisation assay• Assay validation, standardisation and controls• Characterisation and strategy
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1313Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1313Consequences of immunogenicity• Efficacy– Factors inducing clinical consequences can be theepitope recognised, affinity, class of the antibody, theamount of antibodies generated, etc.– Capability of being cytotoxic (cell mediated,complement mediated)– Antibodies recognising epitopes on the therapeuticprotein not linked to activity are expected to beassociated with less clinical consequences.– “Neutralising” antibodies, interfering with biologicalactivity by binding to or near the active site, or byinduction of conformational changes, can induce lossof efficacy.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1414Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1414Consequences of immunogenicity• Safety– patients who develop antibodies are more likely toshow infusion-related reaction– the consequence of immunogenicity is product-specific and can elicit unexpected clinicalsymptoms.– Immediate hypersensitivity– Delayed hypersesitivity and immune complexes– Cross-reactivity with an endogenous counterpart
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1515Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1515Consequences of immunogenicity• Immunogenicity and Clinical Development– Immunogenicity assessment should be part of theclinical trials, since the correlation to clinical efficacyand safety is important– Several factors such as dose, schedule and treatmentmodalities influence the development of an immuneresponse against a therapeutic protein– For products intended for chronic use, it may benecessary to study the evolution and persistence of anobserved immune response
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1616Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1616Consequences of immunogenicity• Consequences on pharmacokinetics of theproduct– Influence of non-neutralising antibodies– Methodology aspects to assess comparability ofimmunogenicity potential as part of acomparability exercise– Applicants should make an effort to select ahomogeneous and clinically relevant patientpopulation that allows for such comparisons.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1717Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1717Risk Management Plan (RMP)• The applicant should present a risk management plan inaccordance with current EU legislation and CHMPGuideline on Risk Management Systems for MedicinalProducts for Human Use (EMEA/CHMP/96268/2005).• The extent of data on immunogenicity that can be obtainedduring the clinical development programme of abiotechnology-derived product before approval depends onthe event rate, driven both by the immunogenic potential ofthe protein and the rarity of the disease.• Therefore, further systematic immunogenicity testing mightbecome necessary after marketing authorization, and may beincluded in the Risk Management Plan.• For planning immunogenicity assessment in the postmarketing setting, the same recommendations apply asdiscussed in previous sections of this guideline.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1818Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1818Annex 1• Further details on methods for assessment andcharacterisation of immunogenicity– Types of antibody assays• Screening assays• Assays for confirming antibody positivity• Assays for dissecting the specificity• Neutralization assays• Assays for assessing cell-mediated immune responses• Assay characteristics• Standardisation, reference materials, well characterizedcontrols and assay validation, interpretation of Results
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1919Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1919Immunogenicity of biologicals
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2020Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2020Product-specific guideline
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2121Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2121Immunogenicity of MoAbs• This guideline addresses issues relating to theunwanted immunogenicity of monoclonalantibodies (mAbs) intended for clinical use.• These include factors impacting on:– immunogenicity of mAbs,– clinical consequences of immunogenicity– assay related problems, assessing neutralizingantibodies induced by mAbs– consideration of a risk-based approach for theevaluation of immunogenicity of mAbs.
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2222Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2222Specific Issues• While many aspects of immunogenicity of mAbsare not different from those for other therapeuticproteins, there are several aspects that requiremore specific considerations.• some specific aspects of immunogenicity areexclusively or primarily relevant for mAbs ornovel mAb derivatives (e.g. Fab fragments, scFv,nanobodies, minibodies)• This guideline considers the major quality andclinical aspects that are important for adequatelyaddressing the immunogenicity of MoAbs
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2323Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2323Antibodies anti-MoAbs• Detection of antibodies against mAbs is oftenmore problematic, difficult and can be technicallychallenging.– Presence of mAb product in samples for analysis– Confirmatory Assays– Controls• Assessing the neutralising capacity of antibodiesinduced against mAbs– Mechanism of action of the MoAb (Complement, cells)• Immunogenicity risk management of mAbs
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2424Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2424Risk identification• Prior knowledge• Mab structure– the immune response is predominantly anti-idiotypic (as the complementarity determiningregions - CDR - are hypervariable in sequence– Hidden epitopes and new epitopes in conjugatedMoAbs– Impurities and other quality attributes• Mechanism of action• Clinical factors (age, previous exposure, etc.)
    • Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2525Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2525Conclusions• Immunogenicity of biologicals is a well knowphenomenon• However mechanisms involved are very complex anddeserve specific investigations and scientificapproaches• The nature of the induced immune response needs tobe clarified and it impact on safety and efficacy shouldbe understood (neutralising vs non-neutralisingantibodies)• Trials available at the time of the MAA may not belarge enough to identify less frequent patients capableof mounting an immune response against the product.• Risk management Plan must take into account allpotential issues linked with immunogenicity.