Understanding immune responses against viral vectors is essential for the development of AAV-based gene therapies. Pre-existing immunity in the form of capsid-specific antibody can neutralize AAV upon dose administration resulting in attenuated therapeutic efficacy. Following administration of valoctocogene roxaparvovec, an AAV5-mediated gene therapy for the treatment of Hemophilia-A, both humoral and cellular responses specific for AAV capsid develop but have not been consistently associated with clinical safety or efficacy parameters.

During drug development, the immunogenicity issue is an essential part, but the introduction of sustainable routines has not been fully implemented in clinical practice. If used optimally, however, measuring drug and anti-drug antibodies (ADA) level have the potential to lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. How, will be discussed in this talk.

Throughout development of a therapeutic protein, the immunogenicity assay validation history can become substantial. This volume of work may confound review of clinical immunogenicity within the Biologics License Application, thus, leading to questions and information requests from regulators. Utilization of a new document, the Method History Report, has streamlined communication of the assay validation history and authoring of the Integrated Summary of Immunogenicity.

Harnessing the power of the immune system has revolutionised treatment options for patients.  However there are concerns about unwanted immune responses leading to serious adverse events.  Regulatory agencies require an assessment of a biotherapeutic’s potential to trigger these unwanted responses. This presentation will focus on solutions to address the potential for unwanted immune responses and why doing so early in candidate selection can have a very positive impact on development time.

Bispecific antibodies (bsAbs) are a novel class of antibodies that aim to improve drug efficacy by simultaneously working on two targets. Compared to the conventional monospecific antibody therapeutics, bsAbs have a relatively shorter development history. This presentation will use two case studies to discuss the benefits of using integrated approaches to characterize immunogenicity findings of bsAbs.

Understanding immunogenicity of transgenes and AAV capsids is key to fully deciphering the potential of gene therapy. Pre-existing and treatment-induced immune responses are big hurdles to overcome to ensure safe, durable, efficacious treatment for a range of genetic diseases. This presentation discusses bioanalytical methods for measuring humoral, innate, and adaptive immunity associated with genomic medicines.

This talk will discuss the interference by drug and target in assays for the detection of binding (ADA) or neutralizing (Nab) anti-drug antibodies and review approaches that have been employed to eliminate it. Some of the considerations covered include relevant concentrations of ADA, drug and target, affinity of natural ADA versus positive control, effects of acid dissociation and reporting of results generated in the presence of excess drug or target.

Highly sensitive iLite^® reporter assay, providing a highly sensitive, rapid, precise method for quantifying NAb response to a wide range of recombinant AAV vectors.

The assay is based on a packaging cell line expressing a recombinant virus, containing a tag sequence within the ITRs and a serotype-specific cap gene recognized specifically by a reporter cell line stably transfected with a luciferase reporter-gene placed under the control of an AAV-responsive chimeric promoter.

The 2019 FDA guidance for immunogenicity testing emphasizes the importance of including an Integrated Summary Report of Immunogenicity in BLA submission. At Merck, we've successfully established an integrated immunogenicity strategy focusing on specific aspects at different development stages. I'll present several case studies to elaborate our risk-based immunogenicity strategy, demonstrate some challenges in ADA assay development, and exemplify how to evaluate immunogenicity data in the context of clinical relevance.

Immune Checkpoint Inhibitors (ICIs) revolutionize the cancer treatment landscape due to their impressive therapeutic results in patients with advanced malignancies. The MOA for ICIs suggested a robust ADA response. However, real clinical experience indicated that the risk of developing clinically relevant ADA response against ICIs is low and may not correlate with their MOA. This presentation will summarize the main lessons learned about the clinical relevance of ADA against ICIs.

Methods for prediction of HLA antigen presentation have improved substantially over the last years, and further steps for improved T cell immunogenicity prediction require consideration of T cell specificities. In my talk, I will outline recent progress in predicting T cell receptor specificities, and demonstrate how performance for prediction of protein drug T cell immunogenicity can be boosted by incorporating features of self-similarity and T cell tolerance.

This presentation describes the construction and characterization of a statistical model to predict the incidence of anti-drug antibodies. The model was trained and evaluated using a set of over 50 clinically assessed monoclonal antibodies and integrates information from an antigen presenting cell internalization assay, an HLA-II peptide presentation assay, and a large human antibody repertoire database.