Reducing Immunogenicity by Design: Approaches to Minimize Immunogenicity of Monoclonal Antibodies

Abstract

Monoclonal antibodies (mAbs) have transformed therapeutic strategies for various diseases. Their high specificity to target antigens makes them ideal therapeutic agents for certain diseases. However, a challenge to their application in clinical practice is their potential risk to induce unwanted immune response, termed immunogenicity. This challenge drives the continued efforts to deimmunize these protein therapeutics while maintaining their pharmacokinetic properties and therapeutic efficacy. Because mAbs hold a central position in therapeutic strategies against an array of diseases, the importance of conducting comprehensive immunogenicity risk assessment during the drug development process cannot be overstated. Such assessment necessitates the employment of in silico, in vitro, and in vivo strategies to evaluate the immunogenicity risk of mAbs. Understanding the intricacies of the mechanisms that drive mAb immunogenicity is crucial to improving their therapeutic efficacy and safety and developing the most effective strategies to determine and mitigate their immunogenic risk. This review highlights recent advances in immunogenicity prediction strategies, with a focus on protein engineering strategies used throughout development to reduce immunogenicity.

Nonclinical immunogenicity risk assessment for knobs-into-holes bispecific IgG 1 antibodies

“…As mentioned previously, and extensively reviewed elsewhere, 17 , 19 each method used has inherent limitations that may lead to false-positive or negative predictions. For example, T cell epitopes detected by MAPPs include parental constant domain sequences that seem likely to be tolerized as self-peptides, 21 i.e., false positives.…”

Revival of Bioengineered Proteins as Carriers for Nucleic Acids

“…Considering that body fluids contain abundant endogenous proteins and protein complexes that do not provoke an immune response, it might be possible to engineer a protein complex to mimic the natural immune tolerance. 78 Viruses protect and regulate their genome from the moment of formation until the delivery into the target organelle, e.g., the nucleus. Analogously, nonviral DNA delivery systems will have to achieve this as well in order to effectively cross the cytoplasm and shuttle the DNA into the nucleus.…”

“…Such responses may occur, even with proteins of human origin, due to factors such as non-native folding, aggregation, and mislocalization of the protein. Considering that body fluids contain abundant endogenous proteins and protein complexes that do not provoke an immune response, it might be possible to engineer a protein complex to mimic the natural immune tolerance …”