The Lower Hinge: A New Control Hub for Antibody Design

Researchers at Science Tokyo have identified the lower hinge of immunoglobulin G (IgG) antibodies as a critical structural and functional control hub. This part of the antibody, previously less studied, plays a significant role in determining antibody structure and immune activity.

The discovery offers new possibilities for designing next-generation antibody therapies.

Unveiling the Mechanism: Deleting a Single Amino Acid

A study published in the Journal of Medicinal Chemistry on January 29, 2026, details how deleting a single amino acid in the lower hinge region can transform a full-length antibody into a stable half-IgG1 molecule with altered immune functions.

The research team, led by Associate Professor Saeko Yanaka and graduate student Yuuki Koseki from the Institute of Science Tokyo, collaborated with researchers from Kyushu University, Nagoya University, and the National Institutes of Natural Sciences.

IgG antibodies are Y-shaped proteins that are the most common type of antibody in the bloodstream, making up about 75% of circulating antibodies. They consist of two Fab regions that bind to antigens and an Fc region that signals to the immune system, all connected by a flexible hinge.

From Full-Length to Half-IgG1: The Pro230 Deletion

The study systematically deleted residues in the lower hinge region of trastuzumab, a humanized IgG1 antibody used in cancer therapy. Deleting a single proline residue (Pro230) resulted in the formation of a 75 kDa half-size antibody, termed half-IgG1. This modification disrupted the normal disulfide bonding pattern, leading to unstable heavy chain linkage.

Imaging studies showed that the relative orientation of the Fab and Fc regions changed, with the Fc region rotating inward. This rotation likely interfered with the Fc region's ability to form its typical dimer.

Maintaining Binding, Altering Signaling

Despite these structural changes, the half-antibody maintained the ability to bind the high-affinity immune receptor FcγRI, though it engaged in immune signaling less efficiently than a full-length antibody.

These findings suggest that the lower hinge is crucial for maintaining the antibody's shape, stability, and overall function.

The researchers propose that these insights provide a framework for engineering antibody variants with precisely tailored immune effects, potentially beneficial for treating diseases such as cancer and autoimmune conditions.