Regulator feedback on the immunogenicity risk assessment of monoclonal antibodies

Determine what methods were used to study the immunogenicity profile of monoclonal antibodies and how the regulators assessed them.


The FDA and EMA published guidance documents on the immunogenicity of therapeutic proteins but examples of immunogenicity studies used to support regulatory decisions and the regulators’ feedback would help ensure immunogenicity risks are properly addressed early on.

Features Used

  • Content Collection
  • Keyword Search
  • Label Search
  • Result Analysis
  • Study Design


Identify guidance documents on immunogenicity, then identify monoclonal antibodies described in these guidance documents and the recommended methodologies related to them. Use these methods to query approved monoclonal antibody review packages and get examples of associated regulator feedback.


Set document category filter on guidelines and agency filter on FDA and EMA


Search for “immunogenicity”


Identify list of recommended immunogenicity assessment methods


Filter on product sample of interest


Run queries to identify methods more commonly used


Identify and analyze feedback on the immunogenicity assessments conducted for these products


FDA and EMA have issued guidance documents on the topic of immunogenicity assessment. When searching all FDA and EMA guidances, 335 documents were found to be related to immunogenicity based on a content match. 14 of them were based on a title match, including 9 final documents and 5 drafts.

From these guidance documents, the methods recommended to screen for immunogenicity in the preclinical and clinical settings were identified. Nine search queries were designed to find content related to each immunogenicity assessment method. The queries were used to determine which methods were used in the development of 19 monoclonal antibody products currently on the market.

Across all FDA and EMA approved products the queries identified a combined total of 477 products including 15 of the 19 monoclonal antibodies.

Table 1: Top matching products by mechanism of action

Mechanism of ActionNo. of Products
Biological Response Modifiers17
Tumor Necrosis Factor alpha Receptor Blocking Activity12
Antibody-Receptor Interactions12
HER2/Neu/cerbB2 Antagonists10
CD20-directed Antibody Interactions8
Receptor Activity Modifying Protein Agonists8
Tumor Necrosis Factor Receptor Blocking Activity6
Enzyme Interactions6
Vascular Endothelial Growth Factor Inhibitors5
Antibody Interactions5
Enzymatic Activity5
Programmed Death Receptor-1-directed Antibody Interactions4
Vascular Endothelial Growth Factor Receptor Inhibitors4
Vascular Endothelial Growth Factor-directed Antibody Interactions4
Interleukin-23 Antagonists4
Insulin Receptor Agonists4
Glucagon-like Peptide-1 (GLP-1) Agonists4
HER1 Antagonists3
Complement Inhibitors3
Enzyme Activators3

Two queries matched with 11/19 products while 4 queries did not match with any products. The two top matching queries were for immunogenicity assessments using (1) Enzyme Linked Immunosorbent Assay (ELISA) and (2) Electrochemiluminescence (ECL). Together these two methods were used in 15 out of the 19 monoclonal antibodies.

Feedback from the regulators on the assessment of immunogenicity was identified across 244 documents related to 14 of the 15 monoclonal antibodies identified in the previous step. Analysis of the feedback revealed that 61% was related to imposed post-marketing commitments or requirements and 39% to pre-submission exchanges with the regulators. Validation and sensitivity were discussed in 90% of these cases.

Figure 1: Topics of discussion with the regulators on immunogenicity assessments