Protein heterogeneity and the immunogenicity of biotherapeutics

Category: Review Article
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The human genome (HG) is comprised of ~ 20,000 open reading frame (ORF) genes; however the human proteome (HP) is orders of magnitude greater due to alternate ORF gene splicing (AS), errors in transcription or translation, the addition of co-and post-translational modifications (CTM; PTM) etc. A recent guestimate suggested that each ORF may be translated to generate 100 structurally distinct proteins, within the outbred human population [1]. Protein and glycoprotein (P/GP) molecules exist in vivo as discreet entities within complex multi-component media, e.g. plasma, cell sap etc. and exert their function(s) through specific interactions with target/receptor molecules. In health each individual expresses a unique proteome and personal integrity demands immunological tolerance to all self-molecules. Ordered aggregation of monomer molecules may be essential for normal function; however, inappropriate, or non-native, aggregation is demonstrable and implicated in the pathogenesis of numerous diseases and may give rise to the generation of autoantibodies [2,3]. Similarly, denaturation and aggregation of protein therapeutics may render them immunogenic and result in the development of anti-drug/anti-therapeutic antibodies (ADA/ATA).

The thriving biopharmaceutical industry requires production of recombinant P/GPs having structural fidelity with a selected endogenous molecule; therefore, structural variants generated during production, purification, formulation and/or delivery is a major concern and equates to potential immunogenicity [2,3]. Practise has shown that pharmacovigilance must be exercised over the life time of an established drug since incidences of adverse events have been reported for drugs long established in the clinic, e.g. insulin [4] and erythropoietin (EPO) [5]. Loss of efficacy is frequently due to the development of ADA/ATA that neutralise therapeutic activity [6,7]. The development of ADA suggests the presence of structurally altered/denatured molecules that are recognized as “foreign” (non-self) by the patient’s immune system i.e. are immunogenic. In this mini review I shall discuss properties of native and recombinant P/GPs that have to be controlled throughout the production and administration of recombinant P/GP therapeutics; illustrated for EPO and antibody therapeutics.

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