title: Immunogenicity of Biotherapeutics: Causes and Association with Posttranslational Modifications.
abstract: Today, potential immunogenicity can be better evaluated during the drug development process, and we have rational approaches to manage the clinical consequences of immunogenicity. The focus of the scientific community should be on developing sensitive diagnostics that can predict immunogenicity-mediated adverse events in the small fraction of subjects that develop clinically relevant anti-drug antibodies. Here, we discuss the causes of immunogenicity which could be product-related (inherent property of the product or might be picked up during the manufacturing process), patient-related (genetic profile or eating habits), or linked to the route of administration. We describe various posttranslational modifications (PTMs) and how they may influence immunogenicity. Over the last three decades, we have significantly improved our understanding about the types of PTMs of biotherapeutic proteins and their association with immunogenicity. It is also now clear that all PTMs do not lead to clinical immunogenicity. We also discuss the mechanisms of immunogenicity (which include T cell-dependent and T cell-independent responses) and immunological tolerance. We further elaborate on the management of immunogenicity in preclinical and clinical setting and the unique challenges raised by biosimilars, which may have different immunogenic potential from their parent biotherapeutics.
authors.affiliation: Biocon Research Limited, Research & Development, Bangalore, Karnataka 560099, India.
authors.forename: Anshu
authors.identifier: 0000-0002-1362-1629
authors.initials: A
authors.lastname: Kuriakose
authors.affiliation: Biocon Research Limited, Research & Development, Bangalore, Karnataka 560099, India.
authors.forename: Narendra
authors.initials: N
authors.lastname: Chirmule
authors.affiliation: Biocon Research Limited, Research & Development, Bangalore, Karnataka 560099, India.
authors.forename: Pradip
authors.identifier: 0000-0002-5272-0478
authors.initials: P
authors.lastname: Nair
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001688:Biological Products / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology* / Q000627:therapeutic use; D059451:Biosimilar Pharmaceuticals / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D019468:Disease Management; D006801:Humans; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D001688:Biological Products; D059451:Biosimilar Pharmaceuticals; D011994:Recombinant Proteins