Capacity to induce undesirable immune responses is a common feature of all biotherapeutics, whether they be peptides, various types of therapeutic proteins, or ATMP-modalities such as nucleic acid entities for gene therapy or cell-based therapeutics. Considerable resource needs to be applied during clinical development to evaluate impact on biodistribution, efficacy and safety in relevant therapeutic settings. In some cases, elevated immunogenicity relative to competitor products can compromise outcomes when allied to other concerns1.

Because the immune response to investigational biotherapeutics is dependent on intrinsic structural properties, risk minimization tools can be applied at the lead candidate selection stage to inform the relative scale of risk and de-immunization strategies2, 3. Many extrinsic factors, including choice of host expression system and drug product formulation, can introduce incremental risk of immunogenicity. To a large extent, these risks can be identified and mitigated at the earliest stages of development4, thereby avoiding painful decisions to terminate a program following completion of expensive clinical studies. Iterative risk assessment during the development of novel biotherapeutics then represents a critical enabling tool for resource allocation and stage-gate decision making.

Understanding regulatory standards for bioanalytical methodology can also make a critical difference in acceptability of results, such that data interpretation requires an integrated approach that balances overly sensitive signal detection with impact on relevant clinical parameters. Presentation of results in regulatory submission needs to reflect both the specific properties of the investigational product and benefit vs. risk for the intended therapeutic use.

At NDA we use a dedicated multi-disciplinary team of subject matter experts who understand the scientific rationale, the underlying mechanistic approaches and can provide timely and critical feedback to support an integrated development and regulatory strategy; relevant questions are anticipated and addressed at successive stages of development; and the NDA model for data presentation5 has been well received by EMA and FDA. Most importantly, working in close collaboration with technical providers means that state-of-art tools are applied at the right time – and results are interpreted in an objective and effective manner.

To learn more about how Paul and NDA can support your company contact us at or see our website


  1. Pfizer discontinues global development of bococizumab, its investigational PCSK9 inhibitor; Press release dated Tuesday, November 01, 2016, available at accessed on 3 June 2020
  2. Jawa V, Cousens LP, Awwad M, Wakshull E, Kropshofer H, De Groot AS. T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation.
  3. Spindeldreher S, Maillère B, Correia E, et al. Secukinumab Demonstrates Significantly Lower Immunogenicity Potential Compared to Ixekizumab. Dermatol Ther (Heidelb). 2018;8(1):57‐68.
  4. Paul Chamberlain & Bonita Rup. Immunogenicity Risk Assessment for an Engineered Human Cytokine Analogue Expressed in Different Cell Substrates. The AAPS Journal 2020, 22: 65
  5. Paul Chamberlain. Effective presentation of immunogenicity risk assessments and related data in regulatory dossiers. Bioanalysis 2019, 11 (17), 1581-1592.
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Paul Chamberlain

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