Deimmunization of protein therapeutics - Recent advances in experimental and computational epitope prediction and deletion

Abstract

Biotherapeutics, and antimicrobial proteins in particular, are of increasing interest for human medicine. An important challenge in the development of such therapeutics is their potential immunogenicity, which can induce production of anti-drug-antibodies, resulting in altered pharmacokinetics, reduced efficacy, and potentially severe anaphylactic or hypersensitivity reactions. For this reason, the development and application of effective deimmunization methods for protein drugs is of utmost importance. Deimmunization may be achieved by unspecific shielding approaches, which include PEGylation, fusion to polypeptides (e.g., XTEN or PAS), reductive methylation, glycosylation, and polysialylation. Alternatively, the identification of epitopes for T cells or B cells and their subsequent deletion through site-directed mutagenesis represent promising deimmunization strategies and can be accomplished through either experimental or computational approaches. This review highlights the most recent advances and current challenges in the deimmunization of protein therapeutics, with a special focus on computational epitope prediction and deletion tools.

Keywords: ABR, Antigen-binding region; ADA, Anti-drug antibody; ANN, Artificial neural network; APC, Antigen-presenting cell; Anti-drug-antibody; B cell epitope; BCR, B cell receptor; Bab, Binding antibody; CDR, Complementarity determining region; CRISPR, Clustered regularly interspaced short palindromic repeats; DC, Dendritic cell; ELP, Elastin-like polypeptide; EPO, Erythropoietin; ER, Endoplasmatic reticulum; GLK, Gelatin-like protein; HAP, Homo-amino-acid polymer; HLA, Human leukocyte antigen; HMM, Hidden Markov model; IL, Interleukin; Ig, Immunoglobulin; Immunogenicity; LPS, Lipopolysaccharide; MHC, Major histocompatibility complex; NMR, Nuclear magnetic resonance; Nab, Neutralizing antibody; PAMP, Pathogen-associated molecular pattern; PAS, Polypeptide composed of proline, alanine, and/or serine; PBMC, Peripheral blood mononuclear cell; PD, Pharmacodynamics; PEG, Polyethylene glycol; PK, Pharmacokinetics; PRR, Pattern recognition receptor; PSA, Sialic acid polymers; Protein therapeutic; RNN, Recurrent artificial neural network; SVM, Support vector machine; T cell epitope; TAP, Transporter associated with antigen processing; TCR, T cell receptor; TLR, Toll-like receptor; XTEN, “Xtended” recombinant polypeptide.