Beyond Efficacy: Ensuring Safety in Peptide Therapeutics through Immunogenicity Assessment

Abstract

Peptides are gaining remarkable popularity in clinical diagnosis and treatment due to their high selectivity and minimal side effects. Over 11% of all new pharmaceutical chemical entities authorised by the FDA between 2016 and 2024 were synthetically manufactured peptides. A critical factor that can potentially limit the efficacy and safety of peptide-based therapeutics or biologics is immunogenicity, defined as an unintended or adverse immune response to a protein or peptide therapy. This response may be triggered by the peptide itself or by impurities in the production or formulation steps, leading to the production of antidrug antibodies (ADAs). To address this, current regulatory guidelines require the assessment of risks in market authorization applications, which include identifying drug impurity levels and immunogenicity. The development and critical evaluation of appropriate immunogenicity assays is therefore highly warranted. Such assays must consider the fine complexities of the immune response, as well as its variation within the human population. Moreover, immunogenicity testing is expected to remain a priority as the shift toward greener chemistries in peptide synthesis may require reassessment of novel impurities in peptide formulations.

Keywords: ADAs; green chemistry; immunogenicity assessment; impurities; peptides.

FIGURE 1

Percentage of different classes of novel therapeutics approved by the FDA in the span of 2016–2024 of which TIDES (peptides and oligonucleotides) attribute for 11.4% (48 out of 420 total drugs) [6, 7]. Antibody‐drug conjugates (ADCs).

FIGURE 2

Assessment of immunogenicity risk of biotherapeutic peptides at different stages of the activation pathway of adaptive immune responses through computational methods (in silico) and in vitro assays for analysis of PBMC including DC, T and B cell cultures. Created with BioRender.com.

FIGURE 3

Bone‐thymus‐liver humanization surgery of SCID mice. Mice that had undergone sublethal radiation (immunodeficient) were implanted with human foetal liver and thymus tissue inside the kidney capsule. They were also given intravenous injections of pure CD34⁺ stem cells that had been isolated from the human foetal liver via magnetic positive selection to yield humanised mice [47]. Created with BioRender.com.