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Monoclonal Antibody Dimers Induced by Low pH, Heat, or Light Exposure Are Not Immunogenic Upon Subcutaneous

Grzegorz Kijanka1, Jared S Bee2, Mark A Schenerman2

  • 1Division of BioTherapeutics, Leiden University, Leiden, the Netherlands.

Journal of Pharmaceutical Sciences
|April 29, 2019
PubMed

The presence of protein aggregates is commonly believed to be an important risk factor for immunogenicity of therapeutic proteins. Among all types of aggregates, dimers are relatively abundant in most commercialized monoclonal antibody (mAb) products. The aim of this study was to investigate the immunogenicity of artificially created mAb dimers relative to that of unstressed and stressed mAb monomers. A monoclonal murine IgG1 (mIgG1) antibody was exposed to low pH, elevated temperature, or UV irradiation to induce dimerization. Dimers and monomers were purified via size-exclusion chromatography. Physicochemical analysis revealed that upon all stress conditions, new deamidation or oxidation or both of amino acids occurred. Nevertheless, the secondary and tertiary structures of all obtained dimers were similar to those of unstressed mIgG1. Isolated dimers were administered subcutaneously in Balb/c mice, and development of antidrug antibodies and accumulation of follicular T helper cells in draining lymph nodes and spleens were determined. None of the tested dimers or stressed monomers were found to be more immunogenic than the unstressed control in our mouse model. In conclusion, both dimers and monomers generated by using 3 different stress factors have a low immunogenicity similar to that of the unstressed monomers.

Keywords:
antibody drug(s)immune response(s)immunogenicitymonoclonal antibody(s)protein aggregation

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