Immunogenicity is one of the factors that may impact efficacy and safety of therapeutic antibodies in patients. Nevertheless, linking immunogenicity assessment to clinical correlates has proved challenging. This presentation will discuss measurement of ADA to therapeutic monoclonal antibodies, and its clinical relevance in terms of drug tolerance, the relation with pharmacokinetics (PK), and the impact on efficacy.

Global clinical studies may utilize multiple bioanalytical labs at various geographical locations for sample analysis. Data comparability among labs is expected to be established before the decision of pooling or comparing immunogenicity results. Currently, there is no clear regulatory guidance on immunogenicity assay cross-validation and acceptance criteria. Here, a case study is presented on an alternative approach when using incurred study samples was not operationally feasible.

Requirements for immunogenicity monitoring are applied to all biotherapeutics, regardless of the molecule’s risk profile. This places an unnecessary burden on low-risk human mAbs. Frequent patient sampling and early collection times increase the detection of clinically irrelevant ADA. Furthermore, NAb assays implemented in registrational studies may add little value when information about low ADA incidence, as well as titer, persistence, PK, PD etc., is available from other assays. For low-risk human mAbs, a new paradigm for immunogenicity testing should be considered.

Monoclonal antibodies (mAbs) are the leading biotherapeutic modality in the IO space. Patients experiencing disease recurrence, non-responders, or those developing resistance may enroll in new clinical trials involving mAbs specific for the same targets. Therefore, bioanalytical challenges may arise, including cross-reactivity in immunoassays from previous therapies, and increase the risk of developing pre-existing ADA. This talk will highlight some of these potential challenges and propose mitigation strategies to overcome them.

Presence of pre-existing antibodies (PRA) to biotherapeutic proteins in drug-naïve individuals is a known phenomenon, of which clinical consequence ranges from no impact to serious adverse effect depending on multiple factors, including but not limited to, drug modality, indication, and subject-specific background. Although evidence for the presence of pre-existing antibody has been initially identified during anti-drug antibody assay development, quantification of PRA incidence in drug-naïve population has become one of the components of preclinical immunogenicity risk assessment strategies. The routine approach to PRA measurement is usually in the form of an ELISA-based assay, in which drug-naïve donors’ diluted serum is co-incubated with the drug in a bridge or sandwich modality. Here we report a novel method, which is based on a surface plasmon resonance (SPR)-measurement of the test molecule binding to immunoglobulins (Ig) purified from drug-naïve subjects’ sera. Isolation of the Ig and concentration normalization eliminates matrix effect and enables comparison across subjects. By using a high-density surface, PRA of a wide range of affinity to the test molecule can be identified, making this approach a sensitive alternative to the ELISA-based methods, and enabling definition of their Ig isotype. The procedure can be performed in a semi-automated fashion to increase efficiency and throughput, and an extensive qualification of the platform shows that this approach is a viable option for including assessment of PRA in a pre-clinical immunogenicity assessment plan.

For over 10 years, bioanalytical scientists have been applying risk-based strategies for immunogenicity assessments of biotherapeutics and there is a good 2019 publication from Paul Chamberlain providing practical advice on how to present this information in regulatory dossiers. However, practices across the industry on the content and presentation of immunogenicity risk assessments may vary and/or may not be done. The goal of this presentation is to provide concrete examples on the presentation of immunogenicity risk assessments and write a fictitious report with help from the audience.

Adeno-associated virus (AAV) gene therapy is a potential treatment for a variety of genetic disorders. A critical challenge for the success of AAV-mediated gene therapy is the host immune response, which may constitute a barrier to long-term efficacy and safety. Careful immunosurveillance following systemic administration of the vector demonstrates that immunomodulation can prevent the humoral response and activation of the complement classical-pathway, triggered by capsid antigen-IgM complexes.