A newly developed hybrid Fc (hyFc) is a non-immunogenic and non-cytolytic Fc with intact Ig structure derived from human IgD and IgG4. It is fused with the human growth hormone (GXD-9) and was evaluated by various biophysical techniques. Two thermal transitions were evident by DSC, reflecting the unfolding of IgG4 and the conjugated protein. The highest T of the initial GXD-9 was 68.17°C and the T of the two domains were around 66°C and 70°C. Although T increased with decreasing concentration, which reflects increasing conformational stability, aggregation issues were still observed by DLS. This might be caused by decreasing or low zeta potential due to a highly complex structure. The protein was dialyzed to various pH (6.2-8.2) values to enhance conformational stability and to overcome aggregation issues. The results of CD spectroscopy were correlated with DSC measurements to evaluate its conformational stability. Changes in secondary structural contents were similar as determined by DSC and DLS. In conclusion, GXD-9 was found to be most stable at pH 7.0. The investigation of the biophysical stability of a hyFc-fusion protein has demonstrated a positive feasibility of developing more stable formulations to facilitate the initial drug development process for further clinical trials.
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