This Research Topic is the second volume of the “Community Series in Understanding Preclinical and Clinical Immunogenicity Risks in Novel Biotherapeutics".
Please see Volume I
here.
Gene and cell-based therapies face novel preclinical and clinical development challenges. Specifically, some safety events related to immunogenicity are due to impurities associated with viral capsids, next-generation gene-modified immune cell therapy constructs, lipid nanoparticles or chemical conjugation associated analytes, foreign epitopes arising due to linkers, signal peptides, as well as bacterial and other viral capsid associated contaminants. Therefore, a better understanding of the impact of the critical quality attributes (CQAs) identified during process development may be beneficial in improving product safety.
A robust preclinical assessment of novel biotherapeutics using ex vivo/ in vitro human blood-derived cells can support the establishment of relevant control strategies and specifications for immunogenicity risks. The selection of critical assays depends on the mechanism of action of the specific product but may include residual cellular DNA or empty viral particles. The extent to which these biotherapeutics can cause early innate phase immune responses by engaging pattern recognition receptors (PRRs) like toll-like receptor family (TLRs) and other scavenger and NOD receptors may also influence the assay selection. Therefore, this Research Topic will invite best practices for immunogenicity assays, their development and validation, and novel strategies to mitigate immunogenicity.
This Research Topic will also seek case studies that cover clinical experiences and immunogenicity strategies implemented from previously filed therapies including Zolgensma (spinal muscular atrophy) and Zynteglo (transfusion-dependent ß-thalassemia). Due to the novelty of these therapies, there is currently limited guidance and understanding of the safety and immunogenicity for gene and cell-based therapies. This has led to uncertainty around building a clear plan for Chemistry, Manufacturing, and Controls (CMC) and clinical strategy for Investigational New Drug Application (IND).
We welcome the submission of Review articles and Case Studies that summarize best practices for supporting risk assessments during preclinical development, the choice of analytical techniques for characterizing immunogenicity risks due to CQAs, and their biological relevance. We also welcome Original Research articles which relate to immunogenicity risks due to product CQA in gene-modified cell therapy-based biotherapeutics. The submissions may cover, but are not limited to, the following subtopics:
1) Developing clinical immune monitoring strategies in different arms of the immune system (innate, adaptive, complement activation, etc.)
2) Understanding the CQAs and their impact on overall product safety and immunogenicity
3) Empty capsid characterization and establishing biologically relevant controls based on in vitro and in vivo models
4) Case studies from approved and failed clinical trials
5) Regulatory strategies for Immunogenicity Risk Assessment
6) Immunogenicity liabilities due to next-generation cell and gene therapies. For example, residual impurities from CRISPR-edited gene therapies or engineered capsids generating neo-epitopes driving an immune response or novel promoters/tissue-specific expression of transgenes that change the overall immune tolerance to the transgene
7) Cas9 and immune-related adverse events
8) The immune-stimulating potential of nucleic acid-based modalities such as siRNA, antisense oligonucleotides, and lipid nanoparticle-enveloped nucleic acids
Topic editor Dr. Vibha Jawa is employed by Bristol Myers Squibb. Topic Editor Dr. Narendra Chrimule is employed by AcuImmune, and is CEO, Director, and Co-Founder of Symphonytech Biologics. All other Topic Editors declare no competing interests.