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.
Luca Broggini, Institute of Molecular and Translational Cardiology, San Donato Milanese, Milan, Italy

Main Body of the Abstract
Systemic immunoglobulin light chain (AL) amyloidosis is a protein misfolding disease caused by the conversion of immunoglobulin light chains (LC) from their soluble dimeric functional states into highly organized amyloid fibrils. Fibrillar deposition of LCs severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. In addition to fibrillar deposition, a further important pathogenic factor is represented by the direct toxicity of soluble pre-amyloid LCs. With the goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we describe the identification and molecular determination of five llama-derived nanobodies (Nbs) directed to H3, an amyloidogenic LC from an AL patient with severe cardiac involvemen. We demonstrated that the Nbs complexed to H3 abolish LC toxicity in the C. elegans in vivo model. We showed that Nbs stabilize H3 native fold and that they bind to their target with affinities in the nanomolar range. Finally, crystal structures of H3-Nb complexes show that Nbs form large interaction surfaces with H3 monomeric variable (VL) domains, stabilizing a partially monomeric LC conformation. Overall, our results show that by the formation of a stabilizing complex between soluble LCs and a specific binder, it is possible to abrogate LC cardiotoxicity; moreover, we picture an unreported partially monomeric LC dimer representing a conformation likely specific for amyloidogenic and toxic LCs. Such conformation may be the one directly responsible for the observed soluble cardiotoxicity or at least an obligate step towards the formation of the toxic species.

**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.**
Luca Broggini, Institute of Molecular and Translational Cardiology, San Donato Milanese, Milan, Italy

**Main Body of the Abstract**
Systemic immunoglobulin light chain (AL) amyloidosis is a protein misfolding disease caused by the conversion of immunoglobulin light chains (LC) from their soluble dimeric functional states into highly organized amyloid fibrils. Fibrillar deposition of LCs severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. In addition to fibrillar deposition, a further important pathogenic factor is represented by the direct toxicity of soluble pre-amyloid LCs. With the goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we describe the identification and molecular determination of five llama-derived nanobodies (Nbs) directed to H3, an amyloidogenic LC from an AL patient with severe cardiac involvemen. We demonstrated that the Nbs complexed to H3 abolish LC toxicity in the _C. elegans_ in vivo model. We showed that Nbs stabilize H3 native fold and that they bind to their target with affinities in the nanomolar range. Finally, crystal structures of H3-Nb complexes show that Nbs form large interaction surfaces with H3 monomeric variable (VL) domains, stabilizing a partially monomeric LC conformation. Overall, our results show that by the formation of a stabilizing complex between soluble LCs and a specific binder, it is possible to abrogate LC cardiotoxicity; moreover, we picture an unreported partially monomeric LC dimer representing a conformation likely specific for amyloidogenic and toxic LCs. Such conformation may be the one directly responsible for the observed soluble cardiotoxicity or at least an obligate step towards the formation of the toxic species.

Nanobodies as novel tools to target cardiac light chain amyloidosis PA17 (#23)

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.