Effects of radiation on the stability of monoclonal antibodies and implications for radionuclide labeled monoclonal antibodies in theranostics

Résumé fourni par la source

Radionuclide-labeled antibody drugs (RN-mAbs), monoclonal antibodies (mAbs) labeled with a radionuclide (RN), are used in nuclear medicine for cancer therapy. RN-mAb provides effective cancer therapy using RN-mAb for diagnostics to confirm suitable tissue accumulation and then using another RN-mAb for treatment. Various RNs are used for diagnosis and treatment; however, the effects of radiation, including molecular modifications to mAbs, are poorly understood. Using externally X-ray irradiated cetuximab, this study evaluated the effects of radiation on mAb characteristics, with a particular focus on the Fc region, which is structurally conserved across different antibodies and is critical for maintaining structural integrity and in vivo stability. X-ray irradiation induced local oxidation or deamidation of amino acid residues, including methionine, proline, phenylalanine, threonine, tryptophan, tyrosine, asparagine, and glutamine. These chemical oxidations led to the structural destabilization of the Fc region, accelerated aggregation, and decreased affinity for the Fc receptors FcγRIIIA and FcRn. These results suggest that radiation exposure changes the characteristics of mAb and causes differences in stability and pharmacokinetics among non-labeled mAb, diagnostic and therapeutic RN-mAbs. This study will help clarify the problems related to the clinical and nonclinical use of RN-mAbs and the issues involved in changing the radionuclide to be labeled.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.