(Press-News.org)
The lower hinge of immunoglobulin G (IgG), an overlooked part of the antibody, acts as a structural and functional control hub, according to a study by researchers at Science Tokyo. Deleting a single amino acid in this region transforms a full-length antibody into a stable half-IgG1 molecule with altered immune activity. The findings provide a blueprint for engineering next-generation antibody therapies with precisely tailored immune effects for treating diseases such as cancer and autoimmune diseases.
Antibodies are Y-shaped proteins that help the immune system recognize and eliminate foreign threats such as bacteria and viruses. The dominant antibody in the bloodstream is immunoglobulin G (IgG), which accounts for about 75 percent of circulating antibodies. Its structure is divided into two main functional units connected by a flexible hinge that must work together seamlessly.
A study published in the Journal of Medicinal Chemistry on January 29th, 2026, reveals that deleting a single amino acid in an antibody’s lower hinge can dramatically alter its assembly and immune signaling. The research was led by Associate Professor Saeko Yanaka and graduate student Yuuki Koseki from the Institute of Science Tokyo (Science Tokyo), Japan, in collaboration with researchers from Kyushu University, Japan, Nagoya University, Japan, and the National Institutes of Natural Sciences, Japan.
“To deepen our understanding of the role of the hinge region in shaping IgG1 architecture and function, we systematically deleted residues in the lower hinge region. Our study demonstrates that a single deletion mutation in the hinge region of IgG1 can produce half-IgG1 molecules," says Yanaka.
An IgG antibody has three main structural components. Two matching arms, known as Fab regions, bind to specific antigens, while a stem-like Fc region connects them and relays signals to the immune system.
Connecting the Fab arms to the Fc stem is a short segment called the hinge. Although small, the hinge plays a critical role by allowing the different parts of the antibody to move together. It provides just enough flexibility for the antibody arms to adapt, enabling efficient target capture while maintaining immune signaling.
The IgG hinge has a “mosaic” design, with a rigid central core that holds the two heavy chains together through disulfide bonds, surrounded by more flexible upper and lower hinge segments.
Previous studies have mainly focused on how changes in the upper hinge and central core affect antibody function, overlooking the lower hinge. To investigate the effect of mutations in the lower hinge, the team performed systematic amino acid substitutions in the hinge region of trastuzumab, a well-known humanized IgG1 antibody used to target the HER2 protein in cancer therapy. By deleting a single proline residue (Pro230), they observed the formation of a 75 kDa half-size antibody species, known as half-IgG1. In this configuration, the disulfide bonding pattern was disrupted, and the two heavy chains were no longer stably linked.
Imaging studies revealed that the relative orientation of the Fab and Fc regions had changed. In a normal IgG antibody, the Fc region is arranged in a way that allows its two halves to pair and interact with immune receptors. In the half-antibody, this pairing surface was rotated inward toward the Fab region. This unusual arrangement likely causes the Fab arms to interfere physically, preventing the Fc region from forming its normal dimer.
Despite this disruption, the half-antibody was not completely inactive. It retained the ability to bind the high-affinity immune receptor FcγRI through a single interface. Because FcγRI can engage antibodies with high affinity, even a half-IgG molecule could still trigger immune signaling, although less efficiently than a full-length antibody.
Together, these findings show that the lower hinge plays a decisive role in maintaining antibody shape, stability, and function, leading the researchers to describe it as a “structural and functional control hub” in IgG1 with the potential to design therapeutic antibodies with customized immune effects.
“These insights redefine the role of hinge region and provide a blueprint for engineering antibody variants with tailored effector profiles for autoimmune disease, cancer, and beyond,” says Yanaka.
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About Institute of Science Tokyo (Science Tokyo)
Institute of Science Tokyo (Science Tokyo) was established on October 1, 2024, following the merger between Tokyo Medical and Dental University (TMDU) and Tokyo Institute of Technology (Tokyo Tech), with the mission of “Advancing science and human wellbeing to create value for and with society.”
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