deimmunization

Deimmunization refers to approaches aimed at reducing the immunogenicity of a therapeutic molecule to minimize undesirable immune responses in the recipient. It is particularly relevant for protein-based drugs, enzyme replacements, viral vectors, and gene-editing proteins, where antibodies or T cell responses can reduce efficacy or cause adverse events.

Common strategies include computational and experimental epitope mapping to identify T-cell epitopes; amino acid substitutions to disrupt MHC-binding motifs while preserving function; removal or masking of dominant B-cell epitopes; glycosylation changes; PEGylation or fusion partners to shield epitopes; humanization of non-human proteins; and the use of tolerogenic regimens or immune-modulatory co-therapies.

Preclinical and early clinical studies use in vitro T-cell proliferation assays, cytokine production, animal models, and eventually clinical data to assess immunogenicity. Deimmunization has been explored in contexts such as CRISPR-associated proteins to enable in vivo gene editing with reduced immunity, and in proprietary engineered enzymes where neutralizing antibodies limit repeat dosing.

Challenges include balancing reduced immunogenicity with retained biological activity, risk of creating new epitopes, patient heterogeneity of HLA types, manufacturing constraints, and regulatory considerations. Because immune responses vary among individuals, deimmunization may reduce risk for some patients but not others.