Observation of Heavy-Chain C-Terminal Des-GK Truncation in Recombinant and Human Endogenous IgG4

Therapeutic IgG mAbs have shown presence of three variations of their heavy chain C-termini, including the unprocessed C-terminal lysine, the processed C-terminal lysine, and C-terminal amidation. These variants are also present in endogenous human IgGs, although the level of unprocessed C-terminal lysine is very low. Here we report a new heavy-chain C-terminal variant, i.e., the des-GK truncation, which exists in both recombinant and endogenous human IgG4. The des-GK truncation was found in negligible amount in IgG1, IgG2 and IgG3 subclasses. Observation of a significant level of heavy-chain C-terminal des-GK truncation in endogenous human IgG4 suggests that low level of this variant present in therapeutic IgG4 is unlikely to be a safety concern. & COPY; 2023 The Authors. Published by Elsevier Inc. on behalf of American Pharmacists Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Automated summary

Therapeutic IgG mAbs can have three variations of their heavy chain C-termini, including unprocessed C-terminal lysine, processed C-terminal lysine, and C-terminal amidation. These variants are also found in endogenous human IgGs, with a very low level of unprocessed C-terminal lysine. A new heavy-chain C-terminal variant, called des-GK truncation, has been discovered in both recombinant and endogenous human IgG4. The presence of des-GK truncation in endogenous human IgG4 suggests that its low level in therapeutic IgG4 is unlikely to be a safety concern.