**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Alana Maerivoet, University of Liverpool, Liverpool, United Kingdom

**Main Body of the Abstract**
Current light chain (LC) amyloidosis treatments focus on depleting the underlying plasma cell clone. Alternative treatment approaches currently being explored involves the inhibition of LC aggregation by stabilisation of the native conformer. UCB Biopharma specialises in the production of biologic therapeutics, and have recently directed their attention towards nanobodies, also known as single domain antibody fragments. Working alongside UCB Biopharma, and using their extensive nanobody libraries, this investigation aimed to identify and characterise antibody fragments that target LC domains and promote their stabilisation. Here, using phage-display screening methods, we identified a range of variable heavy (VH) domains that were targeted towards the LCs LEN, SMA and REC. Using a variety of biophysical techniques, such as circular dichroism spectroscopy, differential scanning fluorimetry and surface plasmon resonance, VH1 was characterised to bind and kinetically stabilise all three LCs. The greatest effect was observed upon VH1 binding to the amyloidogenic LC SMA, whereby an >5.5°C increase in thermal stability was noted. This improved stability corresponded to the inhibition of fibril formation, whereby even a 10:1 SMA:VH1 concentration reduced aggregation to baseline levels. X-ray crystallography was utilised to explore VH1’s mechanism of action, with an atomic level resolution structure of the SMA:VH1 complex revealing that binding occurred in a 1:1 ratio, mimicking the dimeric antigen binding site of the native Ig molecule. These results suggest targeting and stabilisation of the LC monomer as a viable approach for further exploration with other amyloidogenic LCs.



Enhanced stabilisation of an amyloidogenic light chain using a tight binding variable heavy domain to mimic the homodimer complex PA28 (#140)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.