Probing the Proteinopathy Component of Light Chain Amyloidosis Pharmacologically

Scripps Research Institute, The, La Jolla CA

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Abstract

1 Immunoglobulin light chain amyloidosis (AL) is a degenerative disease that arises from light chain (LC) 2 misfolding and aggregation. Full-length (FL) LC dimers (FL LC2) are secreted from a clonally expanded plasma 3 cell population in AL. Thus, AL patients suffer from both a plasma cell cancer and an LC misfolding and 4 aggregation-associated proteinopathy that leads to progressive organ deterioration. Currently, AL is treated by 5 chemotherapy drugs that typically kill most but not all of the clonal plasma cells secreting FL LC2. The 6 remaining clonal plasma cells continue to secrete FL LC2’s into the blood, and about 25% of the AL patients 7 die within the first year of treatment, suggesting that mechanistically distinct therapeutic approaches are 8 needed, particularly for patients with cardiac involvement. A kinetic stability assessment of FL LC2 sequences 9 in patient plasma before treatment at the Mayo clinic generated the transformative information that patients 10 with the most kinetically unstable FL LC2’s have a poor chemotherapy treatment prognosis, demonstrating the 11 clinical need for AL drugs that treat the proteinopathy component of AL. 12 The first funding cycle of this grant produced a clinical candidate to inhibit the misfolding and aggregation 13 of kinetically unstable FL LC2s. This small molecule kinetic stabilizer selectively stabilizes natively folded λ FL 14 LC2s relative to the misfolding transition state, significantly slowing misfolding and proteolysis that often 15 enables variable domain aggregation. Phase 1 clinical trials are anticipated to begin in Q1 2025 to test the 16 hypothesis that treating the proteinopathy along with the cancer will lead to better AL patient outcomes. 17 Aim 1 of this proposal seeks to produce second-generation covalent and non-covalent small molecule 18 kinetic stabilizers to stabilize more diverse λ and κ FL LC2 sequences against FL LC2 misfolding, aberrant 19 proteolysis and aggregation. This effort should result in stabilizers that are effective at lower doses and for a 20 wider range of patients. Aim 2 focuses on developing new assays to assess kinetic stability, susceptibility to 21 proteolysis, and aggregation of λ and κ LCs. Mass spectrometry- and subunit exchange-based kinetic stability 22 measurements will be used to assess the efficacy of second-generation small molecule kinetic stabilizers. New 23 assays will also be developed to directly test FL LC2 proteolysis, misfolding, and aggregation with and without 24 treatment with kinetic stabilizers. Finally, this proposal will explore the efficiency of the refolding of non-native 25 FL LC2’s that dissociate from amyloid fibrils, mediated by the current kinetic stabilizer clinical candidate and 26 analogous second-generation kinetic stabilizers. 27 The overall goal is to produce a safe, effective treatment option for AL that slows disease progression 28 beyond what is possible with current chemotherapy regimens. The approach of using a kinetic stabilizer that 29 inhibits FL LC2 misfolding and aggregation is the first to address the proteinopathy component of AL. This 30 project will also introduce new measurements of FL LC2 instability to help predict patient prognosis. 31 32 33