Researchers from the University of Liverpool have identified and characterised antibody fragments that target free light chain (LC) to help treat patients living with AL amyloidosis.
The new research, published in The FEBS Journal, could help to stabilise and prevent their LC antibody aggregation and could also be applied to other forms of the condition, including Alzheimer’s disease.
Estimated to affect five to 12 people per million worldwide every year, amyloidosis is a group of rare, serious conditions caused by the abnormal folding of amyloid proteins that build up in tissue throughout the body.
Currently the most common but rare and severe form of the condition, AL amyloidosis occurs when abnormal LC proteins in the body mutate and gather on the tissues and organs, including the heart, kidneys, liver, spleen, nervous system and digestive tract.
The current treatment can be difficult to tolerate “and diagnosed patients often have a poor prognosis, with the estimated survival time being between six months and three years,” explained Dr Jill Madine, senior lecturer, biochemistry, cell and systems biology, University of Bristol.
Using phage-display screening methods – a form of high-throughput screening that allows large numbers of peptide segments to be screened for binding to a target – researchers identified a variable-heavy (VH) domain called VH1, targeted towards FLCs SMA, LEN and REC.
Each LC is composed of two tandem immunoglobulin domains: one constant (CL) domain and one variable domain (VL), which is important for binding antigen.
Results showed that VH1 was able to bind and kinetically stabilise LCs, which improved the stability of the inhibition of fibril formation of SMA by reducing aggregation to baseline levels and mimicking the dimeric antigen binding site of the native Ig molecule and SMA homodimeric structure.
After testing in three participating AL amyloidosis patients, the FLC concentration was found to be significantly raised, while only SMA and REC were found to be amyloidogenic in vevo.
The findings suggest that VH1 has the potential to therapeutically target AL amyloidosis by stabilising native LCs, improving its stability and preventing the aggregation of VH1 alone.
Madine commented: “We are excited by this finding, which has potential to provide a much-needed treatment for people diagnosed with the condition.”
