Targeting Sec61 to Silence Pathogenic Light-Chain Production in AL Amyloidosis

Unstable immunoglobulin light chains (LCs) secreted by clonal plasma cells drive organ damage in AL amyloidosis, yet no therapy exists to directly suppress their biosynthesis. Here, we targeted the Sec61 translocon to block LC biogenesis. In patient-derived plasma cells, the Sec61 inhibitor mycolactone redirected nascent LCs to proteasomal degradation, inducing proteotoxic stress that synergized with the proteasome inhibitor bortezomib. In vivo , this combination reduced plasma-cell engraftment and LC secretion but caused systemic toxicity, underscoring the need for Sec61 inhibitors with client selectivity, i.e. the ability to block only the translocation of a restricted number of Sec61 substrates. Proteomic profiling of a model patient-derived plasma cell line treated with the synthetic Sec61 inhibitors A317 and A347 revealed intermediate- and narrow-spectrum client selectivity, respectively, while retaining activity against the pathogenic LC. However, unlike A317, the more selective A347 failed to inhibit diverse amyloidogenic LCs in a signal-peptide reporter assay. In primary plasma cells from a cohort of patients with AL amyloidosis, A317 consistently reduced pathogenic LC production while sparing matched non-malignant bone marrow cells. Together, these findings establish Sec61 as a therapeutic target in AL amyloidosis and highlight the need to balance client selectivity with coverage of diverse amyloidogenic LC signal peptides.