MHC-associated peptide proteomics (MAPPs) allows the sequences presented for immune surveillance after natural processing in antigen presenting cells to be precisely defined. Throughput concerns limit implementation at the candidate or later stages of molecule development. This presentation highlights the integration of MAPPs data, along with APC internalization and a large human antibody sequence database, for the construction of a statistical model to predict the incidence of immunogenicity in early development.

Mutations with respect to the germline sequences of human antibodies have been shown to drive immunogenicity, but strikingly many proteins are immunogenic even though their sequences are entirely human. Human sequences can be artificially modified by chemical modifications but there is no indication on their immunogenicity. This talk will highlight the immunological mechanisms involved in these responses in order to anticipate immunogenicity issues.

Cell & Gene Therapy products are designed to modify the expression of defective genes and/or to alter the biological properties of cells and/or tissues to treat rare conditions. Changing the biological characteristics of cells is expected to elicit immune responses in the host that can compromise the safety (e.g. GVHD) and/or block the efficacity of the therapeutic product (e.g. pre-existing anti-AAV antibodies). This presentation will focus on how to identify the immunogenicity risk factors (product-intrinsic, systems biology, conditions of use, patient-related and product quality) to define the best immunogenicity testing and mitigation strategies for CGT product development.

Novel modalities biologics such as CAR T and gene therapy have shown remarkable clinical efficacy and are in development for multiple indications. The complexity of these modalities, as well as the multiple ways they can interact with the human immune system, can make preclinical immunogenicity risk assessment and mitigation challenging. Immunogenicity risk assessment tools developed for biologics (mAbs) can be adapted to evaluate and assess immunogenicity risk of novel modalities biologics.

Gene therapies and cellular therapies use viral vectors as vehicles to deliver gene of interest. There is an immunogenicity risk associated with such vectors as they activate the innate phase (pattern recognition receptors, complement system etc.) and prime and activate the adaptive phase response (mediated by T cells). Based on the nature of transgene and tropism of vector serotype, the risk-based bioanalytical would need to adapt to decide whether humoral or cellular immune response would be needed. 

The development of anti-drug antibodies (ADAs) is an undesirable potential outcome of the administration of biotherapeutics. We have developed a novel method that provides a rapid and simple preclinical test of the immunogenic potential of a new candidate biotherapeutic or biosimilar. Implementation of this approach during biotherapeutic research and development enables rapid elimination of candidates that are likely to cause ADA-related adverse events and detrimental consequences.

Understanding potential immunogenicity risks of your therapeutic candidate is a key part of pre-clinical development. Here we discuss how a panel of healthy donors can be pre-qualified for specific assays and how this donor panel can be used in studies to assess the immunogenicity risk of therapeutics.

Enzyme replacement therapy (ERT) is effective in treating patients with lysosomal storage diseases. These diseases are a result of deficiency in endogenous enzyme activity, which vary in severity, and present unique considerations for immunogenicity of ERTs. Immune responses can widely vary and present challenges to predict which patients will develop a robust immune response. Approaches to identify patients and an overview of immunogenicity mitigation strategies will be discussed.

Predictive tools measuring specific steps of the immune response are used during drug development to decrease the risk of clinical immunogenicity. To assess the performance and help with the interpretation of these tools, control biologics with known rates of clinical immunogenicity are essential. This presentation will use a panel of control biologics to illustrate how preclinical tools could be leveraged to formulate a comprehensive strategy to assess the immunogenicity risk.

In vitro CD4 T cell stimulation has been used as an indicator of immunogenicity risk for biologics. The commonly used in vitro CD4 T cell assays include dendritic cell - autologous CD4 T cell co-culture (DC-T) assay and whole PBMC assay. Here, we report the immunogenicity risk test results using both DC-T and whole PBMC assay for a monoclonal antibody which elicited strong ADA response in a Phase I study.

The utility of tolerance induction using biodegradable antigen-encapsulating carboxylated poly(lactide-co-glycolide) (PLG) nanoparticles (Ag-PLG) as a ‘negative vaccine’ for in treatment of autoimmune diseases will be discussed. The mechanisms underlying Ag-PLG tolerance induction and maintenance via activation of induced Tregs (iTregs) and Tr1 cells for controlling Th1/17-driven animal models of MS and T1D will be presented. Lastly, the safety and efficacy of tolerance using gliadin-encapsulating PLG nanoparticles for prevention of gliadin-specific T cell responses and intestinal pathology in celiac disease patients undergoing gluten challenge will be summarized. 

The presentation will delve into the biochemical and immunological mechanisms associated with increased adjuvanticity and immunogenicity, as observed in chronic inflammatory conditions. Conditions associated with low-grade chronic inflammation sustain a tissue environment enriched in DAMP, pro-inflammatory cytokines and TLR-s-signaling molecules, which increase dendritic cell adjuvanticity. In unison, changes in the MHC II presented immunopeptidome, sustain an auto-reactive T and B cell repertoire which worsen tissue damage and immunological cell death.