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Immunogenicity Integrated

Immunogenicity consulting

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Identification of product-specific risks

Our collective experience encompasses a broad range of product types, from synthetic peptides through multi-specific proteins to advanced therapy medicinal products

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  • Strategic consulting on application of risk-based approach to identify, immunogenicity-related risks from lead-candidate selection stage onwards, including:
    • Intrinsic immunogenic potential associated with molecular features (B-/T-cell epitopes, non-human structural motifs, allogeneic properties)
    • Mode of action and systems biology
    • Choice of expression system, including mammalian, yeasts & plants
    • Product quality attributes and manufacturing changes, including formulation
    • Orthogonal analytical methods for product characterisation and quality control
    • Subject-related factors, e.g. genotypic and phenotypic heterogeneity
    • Dose regimen & route of administration
    • Implications for clinical study design & bioanalytical monitoring
  • Integration of innate and adaptive immune mechanisms with state of immune tolerance and other patient-related variables
  • Translational approach that assesses relationship of immune response to primary and secondary pharmacodynamics
  • Risk prioritization aligned with regulatory expectations for stage of product development
  • Due-diligence for in-licensing opportunities
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Effective risk evaluation / mitigation

Our goal is to define activities for evaluation and mitigation of pertinent risk factors for immunogenicity, thereby building a comprehensive action plan for successful development and commercialisation

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  • Utility of risk minimization tools (in silico, in vitro & ex vivo)
  • Linkage to manufacturing and product quality control strategy:
    • Analysis of product-related variants and process-derived impurities on scale of risk
    • Impact of non-human glycosylation
    • Testing for influence of aggregates and sub-visible particles
  • Development and validation of bioanalytical methods (ADA, NAb, PK, immunophenotyping & biomarker assays):
    • Effective bioanalytical method design and implementation, including practical options to overcome limitations, e.g. specificity, selectivity, sensitivity
    • Diverse platforms for monitoring humoral and cellular immune responses, including ligand-binding & cell-based assays, ELISpot, flow cytometry/FACS, SPR (BIAcore) etc.
    • Orthogonal approaches for Advanced Therapy Medicinal Products (ATMP)
    • Overcoming interference by target, drug or other factors
    • Control of critical reagents
    • Suitability of different candidate positive controls
    • Data analysis, including considerations for assay cut points and pre-existing antibodies
    • Preparation of high-quality documentation
  • Translational interpretation of non-clinical data for benefit-risk to proceed into clinical development
  • Prospective definition of descriptive endpoints for regulatory submissions
  • Design of clinical studies to incorporate adequately extensive sampling schedule for testing relevant bioanalytical and clinical parameters
  • Risk mitigation measures for clinical studies
  • Strategy for managing unexpected results
  • Participation in meetings with regulatory authorities (EU and USA)
  • New therapeutic indications and life-cycle management
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Assessment of clinical impact

We apply an integrated approach to enable a balanced interpretation of the scale of risk for clinically impactful immunogenicity for the intended therapeutic use, thereby providing the most accurate information for regulators and prescribers

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  • Stratification of immunogenicity impact assessment according to:
    • Severity of clinical consequences associated with intended therapeutic use
    • Opportunities for mitigation of identified risks in clinical practice
    • Impact on overall clinical benefit vs. risk
    • Availability of alternative treatment options
    • Weight of evidence vs. uncertainty
  • Analysis of humoral and cellular immune responses in relation to specificity and sensitivity of bioanalytical methodology and relevance to clinical pharmacology
  • Linkage to product quality at different stages of clinical development:
    • Bridging results across pre- vs. post-manufacturing changes, including new drug product formulations
  • Minimizing confounding factors for data interpretation:
    • Pre-existing cross-reactive antibodies
    • Immune tolerance
    • Danger signals for innate immune effector cell upregulation
    • Concomitant immune-modulatory medication
  • Mapping relationships of nature and scale of immune responses to PK, PD, efficacy & safety endpoints
  • Analyses at the individual subject and treatment group levels to estimate “worst-case” outcomes
  • Implications for prescribing information and ongoing risk management
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High-quality regulatory submissions

We apply a sound understanding of current regulatory standards to anticipate and avoid rate-limiting issues by clear and integrated presentation of the relevant data

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  • Interpretation of applicable regulatory guidance, including ICH, WHO, FDA & EMA
  • Risk Assessment for Clinical Trial Applications in EU and USA
    • Systematic approach adapted to the nature of the product and intended therapeutic use, with linkage to product quality control strategy and strategy for bioanalytical methodology and clinical monitoring
    • Enables updating during clinical development
  • Bioanalytical documentation (ADA, NAb, PK, immunophenotyping & biomarker assays) to meet current regulatory standards
  • Briefing materials for Scientific Advice and Advisory Committee meetings
    • Defining strategic objectives
    • Preparation of questions, company positions & supporting information
    • Advocacy role in meetings
  • Integrated Summary of Immunogenicity for MAA / BLA (novel biotherapeutics & biosimilars)
    • Stand-alone module (Section of CTD dossier format) that summarizes the risk-based strategy, bioanalytical methodology and clinical results to enable a full regulatory assessment of immunogenicity for marketing approval
  • Responses to questions arising during regulatory review procedures