When to Incorporate an IRA
Key milestones and scenarios that warrant immunogenicity risk assessment
Immunogenicity risk assessment is not a one-time activity. Top biopharma organizations have IRAs integrated throughout discovery and development, with focused assessments at critical milestones and whenever significant changes occur. Early and proactive assessment helps you anticipate challenges and build a robust assessment and risk mitigation strategy.
Key Development Milestones
Critical points in your development timeline where immunogenicity assessment is most valuable
Early Discovery Through Candidate Selection
Evaluate immunogenicity risk factors early when considering drug targets or therapeutic modalities through selection of lead candidates. Consider sequence liabilities, post-translational modifications, and platform characteristics. In silico and in vitro risk assessment tools can inform candidate ranking and lead selection decisions.
After Sequence Modifications
Any modification to the amino acid sequence (including Fc engineering, affinity maturation, or de-immunization efforts) could warrant re-assessment. Even single amino acid changes can introduce new T-cell epitopes or alter existing immunogenicity risk profiles.
Pre-IND / Before First-in-Human
Develop a comprehensive immunogenicity risk assessment before IND submission. This baseline assessment integrates all available data (sequence analysis, in vitro assessments, product quality attributes, clinical context, etc.) and establishes your clinical immune monitoring strategy.
Platform Changes
Changes to expression system, cell line, or manufacturing platform can affect product quality attributes relevant to immunogenicity. Risk assessment of these changes can include evaluation of potential impacts on aggregation, glycosylation, and other quality attributes.
Manufacturing Process Changes
Process modifications (including scale-up, site transfers, or process optimization) could warrant comparability assessments that should include immunogenicity considerations. Changes to formulation, container closure, or storage conditions also warrant consideration.
Clinical Phase Transitions
Update your risk assessment and integrated summary of immunogenicity (ISI) with emerging clinical data as you progress through development phases. Incorporate ADA incidence data, clinical correlations, and any safety signals to refine your understanding and inform subsequent trial design.
Pre-BLA / Marketing Authorization
Prepare integrated immunogenicity summaries for regulatory submission. This comprehensive assessment synthesizes all data generated throughout development and provides the foundation for product labeling discussions.
Common Trigger Scenarios
Beyond scheduled milestones, these situations often warrant focused immunogenicity assessment
Platform Changes
Moving to a new expression platform, cell line change, or adopting a novel modality format. Each platform has distinct immunogenicity characteristics that need evaluation.
Novel and Complex Therapeutic Formats
Bispecific antibodies, fusion proteins, and other complex formats introduce unique immunogenicity considerations related to novel junctions, increased foreign sequence content, and altered effector functions.
Immune Agonism Risk
Molecules designed to activate immune pathways (checkpoint agonists, cytokines, immunostimulatory targets) require careful assessment of immunogenicity in the context of their intended mechanism of action.
Manufacturing Changes
Process modifications, site transfers, scale changes, or formulation updates that could affect product quality attributes relevant to immunogenicity.
Comparability Exercises
Biosimilar development or post-approval changes requiring demonstration of comparable immunogenicity risk profiles between products or processes.
Unexpected Clinical Signals
Higher-than-expected ADA incidence, loss of efficacy over time, or immune-related adverse events that prompt re-evaluation of your prior immunogenicity risk assessments.
New Patient Populations
Expanding into pediatric, immunocompromised, or other special populations where immunogenicity dynamics may differ from your initial target population.
Regulatory Requests
Questions or requests from regulatory agencies regarding your immunogenicity assessment, testing strategy, or risk mitigation approach.
Our Core Principle: Be Proactive, Not Reactive
The most effective immunogenicity risk management is proactive. Waiting until you encounter a problem can be costly, both in terms of capital, development timelines and the ability to implement effective mitigation strategies.
By integrating immunogenicity risk assessment at appropriate milestones throughout development, you build a comprehensive understanding that supports better decisions, smoother regulatory interactions, and ultimately, better outcomes for patients.
Not Sure If It's Time?
We're happy to discuss your specific situation and help you determine whether an immunogenicity risk assessment would add value at your current stage.
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