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New insights into antibody aggregation are expected to open new avenues for research and therapeutic applications

manhattantribune.com by manhattantribune.com
8 December 2023
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New insights into antibody aggregation are expected to open new avenues for research and therapeutic applications
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Schematic structures resulting from the 3D domain exchange of variable region #4VL (yellow) in the light chain #4C214A (yellow and light gray) of an antibody. The antibody light chain was found to maintain a balance between monomeric and tetrameric states. Credit: Shun Hirota and Takahiro Sakai

Antibodies (immunoglobulins) are Y-shaped proteins that recognize and neutralize specific pathogens. Their ability to target specific molecules or cells has made them promising candidates for future drug development. However, their light chains – parts of the antibody that help recognize and bind to specific antigens – misfold and aggregate, leading to amyloidosis, a disease that causes complications and tissue dysfunction in the body.

In the context of drug development, the aggregation of antibodies can compromise their ability to bind antigens and diminish their therapeutic potential. However, the lack of detailed structural information on its aggregation is one of the factors hindering progress in this area.

Accordingly, ongoing efforts aim to provide detailed reports on the overall structures and their formation mechanisms in order to advance the development of antibody drugs.

In a study published in Natural communicationsa team of Japanese researchers led by Shun Hirota of the Nara Institute of Science and Technology (NAIST), recently provided new insights into the structures formed during the aggregation of antibodies by 3D domain exchange (3D-DS ), a process in which a region of a protein is exchanged between two or more molecules of the same protein.

The 3D-DS process has been observed in various proteins, but not in antibody light chains until the present study.

In their investigation, the researchers used a modified version of the antibody’s light chain. In this modified form, a cysteine ​​residue (Cys), which typically forms a disulfide bond with a heavy chain cysteine, has been replaced with alanine (Ala). This alteration allowed the team to isolate and study structures resulting from 3D-DS in the segment of the antibody contributing to antigen binding.

3D-DS of the antibody light chain involves the formation of dimers (structures consisting of two identical subunits) and tetramers (structures consisting of two dimers with four identical subunits).

“Our study provides the first report on the atomic-level structure of the 3D-DS phenomenon in the variable region of an antibody light chain,” highlights Hirota.

Size exclusion chromatography of the light chain of antibody #4C214A revealed that the antibody exists as individual monomers and four-subunit tetramers. To determine the region where tetramers form, the researchers divided the antibody light chain into a variable region (the Y-shaped tip of the antibody) and a constant region (the middle part of the antibody shaped of Y).

They discovered that the variable region #4VL can switch between monomeric and tetrameric states.

Further analysis using X-ray crystallography and thermodynamic simulations revealed that tetramer formation is driven by hydrophobic interactions occurring between two 3D-DS dimers.

Compared to monomers, tetramers have more rigid β-sheet structures, making them less flexible. The formation of the 3D-DS tetramer may help prevent protein aggregation by decreasing flexibility, thereby potentially avoiding the formation of insoluble aggregates. On the other hand, 3D-DS may promote antibody aggregation.

Hirota concludes: “These findings not only clarify the domain-swapped structure of the antibody light chain, but also help control the quality of antibodies and advance the development of future molecular recognition agents and drugs.

More information:
Structural and thermodynamic insight into the formation of antibody light chain tetramers through 3D domain swapping, Natural communications (2023). DOI: 10.1038/s41467-023-43443-4

Provided by Nara Institute of Science and Technology

Quote: New insights into antibody aggregation should open new avenues for research and therapeutic applications (December 8, 2023) retrieved December 8, 2023 from

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Tags: aggregationantibodyapplicationsavenuesexpectedinsightsopenResearchtherapeutic
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