RARE DISEASE
AL amyloidosis
AL amyloidosis
AL amyloidosis
Synonyms: Light-chain amyloidosis
Synonyms: Light-chain amyloidosis
Synonyms: Light-chain amyloidosis
Drug discovery
26
drugs
With orphan designations
Overview
AL amyloidosis is a systemic disorder caused by misfolded immunoglobulin light chains produced by clonal plasma cells, leading to progressive organ dysfunction. Cardiac and renal involvement are most common, with advanced cardiac disease conferring high mortality. Diagnosis relies on monoclonal protein detection, tissue biopsy with Congo red staining, and mass spectrometry. Treatment targets plasma cell clones to suppress toxic light chain production, combined with organ-supportive care [1][4][6][10].
Categories: rare cardiac diseases, rare hematological diseases, rare neoplastic diseases, rare neurological diseases, rare renal diseases, rare systemic and rheumatological diseases, rare transplant-related disorders
Research Papers
1,617 drug discovery papers about AL amyloidosis, with 2 first-in-class and 22 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,617 drug discovery papers about AL amyloidosis, with 2 first-in-class and 22 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-13 | Amyloidosis and Thoracic Aortic Disease: A Scoping Review.
Background and Objectives: Amyloidosis is a systemic disorder characterized by extracellular deposition of misfolded protein fibrils, most commonly light-chain (AL) or transthyretin-derived (ATTR) ones. Cardiac involvement is well recognized, but large-vessel complications, including thoracic aortic aneurysms (TAA) and dissections, are rare and under-reported. The aim of this review article is to provide insights into pathophysiology, clinical diagnosis and the therapeutic opportunities in amyloidosis-related thoracic aortic diseases. Methods and Materials: The PRISMA Extension for Scoping Reviews (PRISMA-ScR) Guidelines were followed. An extensive search of the available literature in the English language, published between 1 January 2000, and 31 December 2025, in three large-scale scientific databases was undertaken by two independent reviewers. The terms "amyloidosis", "thoracic aorta", "thoracic aortic aneurysm", "aortic dissection", and "aortopathy" were used both as specific items, as well as in MeSH Terms. Studies reporting on the pathophysiology, diagnosis, clinical manifestations, treatment options and prognosis of amyloid deposition on the thoracic aorta were included in the review. Because of the nature of the existing literature, only a narrative review was possible. Results: Twenty-nine studies were included. Owing to the rarity of reporting, data was derived mainly from case reports and series, as well as autopsy studies. Amyloid infiltration of the aortic wall has been associated with medial architectural disruption, degeneration of elastic fibers, impairment of vasa vasorum perfusion, and arterial stiffness, all of which could contribute to aneurysmal dilation and aortic lesions. Amyloidosis management combines targeted anti-plasma cell therapy with supportive care. In AL amyloidosis, melphalan-dexamethasone (MDex) was historically standard, but regimens such as cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and bortezomib, melphalan, and dexamethasone (BMDex) achieve higher complete response rates. Immunotherapy with Daratumumab has shown high overall and complete response rates. Fibril-directed approaches, including doxycycline and epigallocatechin gallate, and monoclonal antibodies, are under evaluation. Acute management of large-vessel manifestations follows conventional protocols, but prognosis is often dominated by underlying cardiac and systemic involvement. Conclusions: Management of thoracic aortic involvement follows standard imaging surveillance and surgical criteria, though operative risk is increased. Multidisciplinary care, early recognition, and individualized risk stratification are essential to improve outcomes, particularly given frequent cardiac involvement.
2026-08-08 | Limited duration of dexamethasone in newly diagnosed AL amyloidosis: impact on response, toxicity, and survival.
Systemic light chain amyloidosis (AL) is a life-threatening disease in which dexamethasone (Dex) is a core therapy but is limited by cumulative toxicity. The optimal duration of Dex, particularly in the era of daratumumab (Dara)-based regimens, is uncertain. We retrospectively analyzed 216 newly diagnosed AL amyloidosis patients (2017-2023). Dex exposure was categorized as limited (≤3 months) or prolonged (>3 months) using restricted cubic spline-derived associations with hematologic response kinetics. Outcomes included hematologic and organ response, toxicity, and overall survival. Median Dex duration was 5.5 months and was similar by Dara use. Overall response rates exceeded 90% at 6 months in both Dex groups. Limited Dex was associated with higher rates of early deep hematologic response (VGPR or better 77.5 vs 56.5%, p = 0.001; CR 42.2 vs 19.4%, p < 0.001), reflecting faster response kinetics, while overall response rates were similar. Among patients receiving limited Dex, Dara was associated with higher 6-month CR rates (66.7 vs 30.4%, p < 0.001) and increased likelihood of achieving CR in multivariable analysis (HR 4.38, 95% CI 2.44-7.85; p < 0.001). Organ responses were similar between groups. Dex-related toxicities increased after 6 months, and hospitalization was associated with worse survival. Limiting Dex exposure was associated with preserved efficacy and reduced toxicity. Prolonged Dex was associated with increased toxicity without improving overall hematologic or organ outcomes, supporting limited Dex duration in frontline AL amyloidosis therapy.
2026-08-08 | AL Cardiac Amyloidosis in Resource-Limited Settings: Diagnostic Challenges and Therapeutic Gaps.
Amyloid light chain (AL) cardiac amyloidosis remains a diagnostic challenge in resource-limited settings. We present 3 cases with varying heart failure presentations, all demonstrating concentric left ventricular hypertrophy with characteristic apical sparing strain pattern on echocardiography. Serum free light chains were consistently abnormal, though immunofixation was negative in 2 patients. Traditional screening biopsies were negative in 2 cases, requiring endomyocardial biopsy for diagnosis. Mass spectrometry for amyloid typing was unavailable; immunofluorescence performed in 1 patient confirmed lambda light chain deposition. All patients received CyBorD-based therapy; 1 patient additionally accessed daratumumab abroad and showed marked improvement, while another died within 6 months on CyBorD alone. These cases highlight the heterogeneous presentation of presumed AL amyloidosis and underscore how diagnostic barriers contribute to delayed diagnosis and more advanced disease at presentation, emphasizing the urgent need for improved diagnostic capabilities and therapeutic accessibility in resource-constrained settings.
2026-08-03 | [Improvement of chylothorax after lymphangiography in AL amyloidosis].
A 74-year-old man presented with leg edema and was found to have nephrotic-range proteinuria. Renal biopsy revealed AL amyloidosis. Subsequent bone marrow examination demonstrated an increase in monoclonal plasma cells accounting for 13% of nucleated cells. Right-sided pleural effusion developed and was confirmed to be chylothorax. Although treatment with daratumumab, lenalidomide, and dexamethasone (DLd regimen) was initiated, the pleural effusion continued to increase. Lymphangiography using ethiodized oil identified a leakage point in the anterior mediastinum. A chest drain was inserted on the following day, and approximately 4 l of chylous fluid was drained. The tube was removed one week later, and pleural effusion did not recur thereafter. Although a hematologic response was achieved, the nephrotic syndrome persisted, and the patient ultimately died. Chylothorax associated with AL amyloidosis is rare and difficult to treat. This case suggests that lymphangiography using ethiodized oil may be both diagnostic and therapeutic.
2026-07-30 | Preventive Effects of Non-sedating and Sedating Histamine H1 Receptor Antagonists Premedication for Subcutaneous Daratumumab-Associated Infusion-Related Reactions: A Prospective Observational Study.
The optimal choice between sedating histamine H1 antagonists (sAHs) and non-sedating histamine H1 antagonists (nsAHs) for preventing infusion-related reactions (IRRs) during daratumumab subcutaneous (DARA-SC) therapy remains unclear. Here, we aimed to compare the efficacy and safety of nsAH and sAH as premedication for DARA-SC therapy. Patients with multiple myeloma or light-chain amyloidosis who received DARA-SC therapy at eight hospitals were enrolled in this prospective, multicenter, observational study. Patients were categorized into nsAH and sAH groups based on their premedication. IRRs and drowsiness were assessed using patient-reported questionnaires, including the Stanford Sleepiness Scale (SSS) and the Japanese Epworth Sleepiness Scale (JESS), at baseline, post-administration (Q2), and before bedtime (Q3). Overall, 104 patients (nsAH, n = 49; sAH, n = 55) were analyzed. No significant differences were observed in the IRR incidence between the nsAH and sAH groups at Q2 (8.2 vs. 9.1%) or Q3 (13 vs. 17%). Conversely, the incidence of new-onset drowsiness at Q2 was significantly lower in the nsAH group (13%) than in the sAH group (32%, p < 0.05). Additionally, the increase in SSS from baseline to Q2 was significantly lower in the nsAH group than in the sAH group (p < 0.05). No significant differences were observed in JESS scores. Thus, nsAH was associated with reduced early post-administration drowsiness and there were no statistically significant differences in IRR preventive effects compared to that for sAH, suggesting that nsAH may reduce sedation without a significant increase in the incidence of IRRs; however, these hypothesis-generating findings warrant verification through future prospective comparative trials.
proteins
2026-06-29 | Siphoviridae phage tails co-enrich with ex vivo amyloids.
Bacteriophages are ubiquitous in the environment and are part of the natural human microbiome. Despite their abundance, the role of the human phagome in health and disease remains poorly understood. Here, we identify phage tails in ex vivo amyloid extracts from patients with lysozyme amyloidosis (ALys) and light-chain amyloidosis (AL). Using cryo-EM analysis of the ALys dataset, automated model building, and database searches, we assigned the observed tubular assemblies to a phage tail tube protein (TTP). Although we cannot fully rule out the possibility of contamination, the presence of phage tails raises the question of whether they bind to and are co-purified with amyloid fibrils. These structures may provide further insight into the potential relationship between phage-derived assemblies and amyloid remodeling, with possible implications for future therapeutic strategies in human amyloidosis.
2026-06-22 | Multifaceted effects of N-glycosylation on amyloidogenic κ light chains in AL amyloidosis.
Light chain (LC) amyloidosis (AL) is a fatal disorder caused by extracellular aggregation of monoclonal immunoglobulin LCs. While both λ and κ isotypes can be involved, κ-LCs account for only ∼20% of cases, and their aggregation mechanisms remain less understood. Recent evidence suggests that N-glycosylation influences κ-LC aggregation and is strongly linked to AL amyloidosis. To investigate this, we examined patient-derived κ-LCs in both glycosylated and unglycosylated forms. Mass spectrometry confirmed the presence of complex-type N-glycans. Biophysical analyses showed that glycosylation enhances structural compactness, stabilizes the native structure, and promotes cooperative unfolding. Glycosylated κ-LCs also exhibited reduced conformational dynamics. Functionally, N-glycosylation significantly improved LC secretion efficiency and extracellular stability. These findings suggest that N-glycosylation acts as a protective factor against amyloid formation and enhances LC accumulation outside the cell. Overall, our study highlights the multifaceted and context-dependent role of N-glycosylation in modulating κ-LC behavior, with important implications in AL pathogenesis.
2026-05-21 | A CDR1 aggregation hotspot controls unfolding kinetics and multimolecular aggregation in IGLV2 light chains.
Immunoglobulin light chains (LCs) exhibit diverse aggregation behaviours that depend sensitively on sequence composition and intermolecular interactions. Understanding how specific residues modulate aggregation kinetics remains a key challenge in elucidating the molecular basis of light-chain amyloidosis. Here, we investigate sequence-dependent aggregation using recombinant λ LCs derived from the IGLV2 gene family. Comparison of two closely related LCs differing by only 16 amino acids revealed striking differences in aggregation behaviour under thermal stress. Bioinformatic analysis identified an additional aggregation-prone segment in the CDR1 region of the aggregation-prone M10 variant, associated with residues Ser33 and Tyr34. Rational substitution of these residues (S33D/Y34S) markedly reduced aggregation while leaving the thermal transition temperature largely unchanged (∼53 °C). Differential scanning calorimetry revealed that the wild-type M10 LC unfolds with a significantly lower apparent activation energy (∼290 kJ/mol) compared with the non-aggregating H9 (∼605 kJ/mol) and the stabilised double mutant (∼560 kJ/mol), indicating reduced kinetic stability. Aggregation of unfolded species showed much weaker temperature dependence (Ea ≈ 10-70 kJ/mol) and exhibited strong concentration dependence consistent with a multimolecular association process. Additional experiments suggest that aromatic interactions involving Tyr34 contribute to the stabilisation of intermolecular assemblies. Together, these results establish a quantitative link between local sequence variation in the CDR1 region, kinetic stability of the LC fold, and aggregation propensity, highlighting how targeted mutations can modulate aggregation behaviour in immunoglobulin light chains.
2026-04-08 | Preventing Pathogenic Dimerization in a Misfolded Antibody Light Chain through the Design of an Inhibitory Peptide.
Immunoglobulin light chain (AL) amyloidosis is the most common form of systemic amyloidosis. The disease correlates with the formation of insoluble aggregates mostly composed of patient-specific antibody light chains, whose hypervariable regions make each case unique and highlight the need for personalized therapeutics. In this study, we focused on a pathogenic homodimer we previously obtained from a patient-derived light chain. By analyzing the dynamics and the interface of this dimer, we identified a peptide with potential inhibitory activity. The peptide was then refined using a computational mutagenesis protocol that iteratively improved its sequence to maximize complementarity with the protein interface, taking into account shape, electrostatics, and hydropathy. The resulting optimized peptide is found to bind the monomer with a binding affinity comparable to that of the full pathogenic interface. These results suggest that the designed peptide could act as an effective antagonist of the pathogenic dimer, and demonstrate that our computational strategy could provide a general framework for designing patient-specific inhibitory peptides against aggregation-prone proteins.
2025-06-02 | The utility of intravenous immunoglobulin infection prophylaxis in patients on anti-CD38 therapies.
BackgroundAnti-CD38 directed therapies have emerged as targeted treatments for multiple myeloma (MM) and light chain (AL) amyloidosis. Intravenous immunoglobulin (IVIG) supplementation has been shown to reduce the risk of bacterial infections by 39% in patients with MM receiving anti-CD38 therapies, with a 72% reduction in grade 3-4 infections. However, there is currently no universal guidance on the optimal population in whom to initiate IVIG prophylaxis to prevent these infectious complications.MethodsThis study was a retrospective, single-centered chart review of eligible patients treated at Yale New Haven Health System (YNHHS) from 2016-2022. Eligible patients included adults with MM or AL amyloidosis treated with an anti-CD38 based regimen. The primary outcome was to compare the rate of pneumonia in patients who have received IVIG as compared to patients who have not. The secondary outcome was to identify the immunoglobulin G (IgG) level associated with an increased risk of pneumonia.ResultsRates of pneumonia were found to be higher within the population receiving IVIG as compared to those not receiving IVIG (29.55% vs. 15.41%, p = 0.05). There were no significant differences in the subgroup analyses including line of therapy, anti-CD38 agent, diagnosis, and IgG disease involvement. There was also no significant correlation demonstrated between baseline IgG level and the occurrence of pneumonia (β1 -0.0001, p = 0.37).ConclusionsIVIG supplementation in patients receiving anti-CD38 directed therapy did not significantly reduce the incidence of pneumonia. Given the lack of benefit with IVIG supplementation, careful consideration must be given prior to administration to limit unnecessary utilization.
cell therapies
2026-07-21 | Efficacy and Safety of BCMA-Targeted Therapies in Relapsed or Refractory AL Amyloidosis: A Descriptive Pooled Analysis.
B-cell maturation antigen (BCMA)-targeted therapies have emerged as promising treatment options for patients with relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. However, comprehensive data on their efficacy and safety remain limited. We conducted a systematic descriptive pooled analysis of published studies reporting outcomes of BCMA-directed therapies including chimeric antigen receptor T-cell (CAR-T) therapies, bispecific antibodies (BsAbs), and antibody-drug conjugate (ADC). The analysis included 256 patients. CAR-T therapy was administered to 89 patients (35%), BsAbs to 82 patients (32%), and ADCs to 85 patients (33%). The pooled overall response rate (ORR) was 83%, with CAR-T demonstrating 92% ORR, BsAbs 89%, and ADCs 68%. Deep hematologic responses (≥VGPR) were achieved in approximately 70% of CAR-T and BsAb recipients and 64% of ADC recipients. Minimal residual disease negativity was documented in 75% of evaluable CAR-T patients and in 86% evaluable BsAb patients with reported data. Organ responses were observed in 30% of evaluable patients, with cardiac responses in 41%. Cytokine release syndrome occurred in 74% of CAR-T and 49% of BsAb patients, predominantly grade 1-2. Grade ≥3 CRS was rare (9% CAR-T, 1% BsAb). Ocular toxicity was the predominant adverse event in ADC recipients (84% any grade, 29% grade ≥3). Grade ≥3 infections occurred in 13% of CAR-T, 20% of BsAb, and 6% of ADC patients. BCMA-targeted therapies result in high response rates with manageable safety profiles in heavily pretreated AL amyloidosis patients, supporting continued investigation and clinical application of these approaches.
2026-06-23 | Autologous stem cell transplantation for AL amyloidosis: a multicenter summary of outcomes 2010-2020.
The role of autologous stem cell transplantation (ASCT) is central in AL amyloidosis and continues to be defined in the era of newer therapies. To evaluate contemporary patient selection, practice patterns, and outcomes, we conducted a retrospective, multicenter study across nine tertiary referral centers, including 1047 patients with AL amyloidosis who underwent ASCT between 2010 and 2020. Most patients (67.9%) received full-dose melphalan conditioning, and 66.5% received pre-ASCT induction therapy, predominantly proteasome inhibitor-based regimens. Day-100 all-cause mortality was 3.0%, representing a substantial improvement compared with historical cohorts. Post-ASCT hematological responses were satisfactory in 75.4% of patients. Among patients with paired assessments, ASCT deepened responses in 56.3% who had not achieved a complete response with induction therapy. With a median follow-up of 5.1 years, the median overall survival was 6.3 years. Independent predictors of inferior survival included age ≥60 years, bone marrow plasma cells ≥20%, pre-ASCT dFLC ≥40 mg/L, elevated cardiac biomarkers, lambda-restricted disease, reduced eGFR and reduced-dose conditioning. In this contemporary cohort, ASCT for AL amyloidosis demonstrated low early mortality, high rates of deep hematologic response, and durable survival in carefully selected patients. These findings support its role as an effective consolidative strategy, while its optimal positioning alongside emerging therapies requires further study.
2026-05-01 | A rare case of renal AHL amyloidosis with marked complement deposition: clinicopathologic and proteomic findings.
Amyloidosis comprises a heterogeneous group of diseases characterized by extracellular deposition of β-pleated-sheet fibrillar proteins that cause progressive organ dysfunction. Among immunoglobulin-related amyloidosis, combined heavy- and light-chain (AHL) amyloidosis is extremely rare, which accounts for approximately 7%. Several studies have demonstrated that complement components can be detected in renal amyloidosis. We report a rare case of renal AHL amyloidosis with marked complement deposition with clinicopathologic and proteomic insights. A 76-year-old woman with a five-year history of microscopic hematuria developed mild renal dysfunction (serum creatinine 1.05 mg/dL) and proteinuria (0.95 g/day). Physical and serologic evaluations showed no evidence of systemic amyloidosis or autoimmune disease. Serum and urine immunofixation detected an IgG-κ M-protein, and bone marrow findings were consistent with monoclonal gammopathy of undetermined significance. Kidney biopsy demonstrated Congo red-positive fibrillar deposits with IgG1, κ, and complement (C3/C1q) staining. Electron microscopy revealed non-branching fibrils measuring 8 to 12 nm in diameter. Because marked complement deposition was observed, fibrillary glomerulonephritis (FGN) was considered in the differential diagnosis. However, negative Dna J heat-shock protein family B member 9 immunostaining raised suspicion for amyloidosis. Mass spectrometry identified IgG1 heavy and κ light chains together with serum amyloid P and apolipoprotein E, confirming IgG1-κ-type AHL amyloidosis. This case illustrates a presentation of AHL amyloidosis with marked complement deposition. Recent study reveals that complement components can be detected in a subset of amyloidosis cases. These features can complicate the differential diagnosis from FGN and highlight the importance of an integrated diagnostic approach combining histopathology, immunostaining, and proteomic analysis. Furthermore, clone-directed therapy targeting the pathogenic plasma cell clone may represent a rational therapeutic strategy for monoclonal immunoglobulin-associated renal disease.
2026-02-05 | Improvement in Cardiac Magnetic Resonance Parameters in Patients With Cardiac Light-Chain Amyloidosis Receiving Anticlonal Cell Therapy.
We sought to evaluate the pattern of changes in cardiac magnetic resonance parameters among light-chain (AL) cardiac amyloidosis patients receiving anticlonal therapy. This study included 35 consecutive patients with AL cardiac amyloidosis (AL CA) from a single amyloidosis center, surviving at least 1 year after diagnosis and undergoing 3T CMR at diagnosis and at 12-months follow-up. Structural, functional parameters, native T1, T2, myocardial and spleen extracellular volume (ECV), and peak left atrial strain (PALS) were recorded. Hematologic response was assessed per current criteria. Mean age was 64.1 years, 57% males and per Mayo staging system 10% were stage I, 32% stage II, and 58% stage III. During follow-up, 54.3% achieved complete hematologic response (CR), 34.3% very good partial response, and 11.4% partial response. Significant changes at 12-month landmark included a reduction in native T1 (1420 ms vs. 1393 ms, P = .001), ECV (46% vs. 43%, P = .004), left ventricular maximum wall thickness (15 mm vs. 13 mm, P = .02), and an increase in stroke volume (76 mL vs. 85 mL, P = .016). Patients with complete hematologic or cardiac response demonstrated improvements in T1 native and ECV. In a subset of n = 12 patients with a repeated follow-up CMR study at a median of 31.2 ± 5.04 months after treatment initiation, a trend towards further reduction in T1 and ECV was noted. In AL-CA patients treated with anticlonal therapy, significant improvement in CMR parameters, correlate with hematologic and organ response and suggest potential cardiac amyloid regression and functional improvement.
2025-12-08 | Up-to-date review on heart transplantation and other advanced heart failure therapies in cardiac amyloidosis patients.
Cardiac amyloidosis (CA) can result in a restrictive cardiomyopathy, and heart transplantation (HT) remains the gold standard treatment for patients with end-stage heart failure secondary to amyloid cardiomyopathy. Although HT was historically contraindicated due to inferior outcomes, survival following HT in patients with CA has significantly improved over recent decades; and outcomes are now similar to those of patients undergoing HT for non-amyloid indications. This improvement has been driven largely by advances in screening for appropriate patient selection and improvement in therapeutic strategies for both immunoglobulin light-chain (AL) and transthyretin (ATTR) amyloidosis. Future directions in HT for CA will hinge on continued optimization of patient selection and refining post-transplant management of extracardiac manifestations.
antibodies
2026-08-10 | IgM Pleural Amyloidosis Diagnosed by Pleural Effusion Cell Block: A Case Report.
Immunoglobulin light chain (AL) amyloidosis is characterized by the systemic deposition of light-chain-derived amyloids. Immunoglobulin M (IgM)-associated AL amyloidosis is extremely rare and clinically distinct. A 70-year-old man presented with dyspnea, bilateral pleural effusion, and mediastinal lymphadenopathy on computed tomography (CT). Amyloid was detected in a pleural effusion cell block and confirmed via an axillary lymph node biopsy. Serum studies and bone marrow findings supported IgM-λ AL amyloidosis associated with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. First-line therapy failed, but second-line therapy reduced pleural effusion, avoiding thoracentesis for one year. A pleural effusion cell block analysis enabled rapid diagnosis with minimally invasive exploration.
2026-07-20 | Histopathological improvement in kidney AL amyloid deposits following daratumumab-based chemotherapy and autologous peripheral blood stem cell transplantation: a case report.
AL amyloidosis is characterized by extracellular deposition of immunoglobulin light-chain fibrils, frequently leading to kidney involvement and progressive organ dysfunction. We report a case of kidney AL amyloidosis secondary to multiple myeloma in which daratumumab-based chemotherapy combined with autologous peripheral blood stem cell transplantation resulted in marked improvement, as confirmed by sequential kidney biopsy. The initial biopsy revealed vascular-dominant amyloid deposition, whereas the second biopsy obtained 2 years later demonstrated a marked reduction in amyloid burden, particularly within the vascular compartments. This histopathological improvement corresponded with hematologic remission and stabilization of kidney function. The observed reduction in tissue amyloid deposits was presumed to result from suppression of amyloidogenic light chains, leading to inhibition of new fibril formation and subsequent tissue remodeling. Our findings provide direct pathological evidence that daratumumab-based combination therapy, through immune-mediated plasma cell depletion, may indirectly promote the regression of amyloid deposits and contribute to functional recovery.
2026-07-09 | Systemic light chain and transthyretin amyloidosis-treatment advancements and future directions.
Once rapidly fatal, neglected, and orphan diseases without approved therapeutic options, systemic amyloidoses are now highly treatable. Basic scientific discoveries regarding the molecular mechanisms of transthyretin misfolding and aggregation have driven the development of drugs for the treatment of transthyretin (ATTR) amyloidosis, with six novel therapies approved since 2018. The combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone was approved for the treatment of light chain (AL) amyloidosis in 2021. Since then, highly effective immunotherapies, such as bispecific T-cell engagers, have been tested in clinical trials in patients with relapsed AL amyloidosis, with unprecedented efficacy. Thus, suspicion of systemic amyloidosis should be raised early in individuals with a suggestive clinical presentation, followed by rapid tissue diagnosis, with appropriate protein typing and prompt commencement of active therapy. These rapid and exciting therapeutic advancements set the stage for this Review on the epidemiology, pathophysiology, and diagnosis of systemic amyloidosis. Through the lens of the molecular mechanisms underlying amyloidosis pathogenesis, we will focus on approved and investigational therapies. We also discuss future directions and challenges concerning a cure for patients with AL or ATTR amyloidosis.
2026-06-18 | Efficacy and safety of BCMA-directed bispecific antibodies in relapsed and/or refractory systemic AL amyloidosis: A systematic review and meta-analysis.
Patients with relapsed/refractory (R/R) systemic light chain (AL) amyloidosis, particularly after daratumumab failure, face limited treatment options and challenging outcomes. B-cell maturation antigen (BCMA)-directed bispecific antibodies (BsAbs) have emerged as a potent strategy in multiple myeloma, yet their collective performance in AL amyloidosis remains to be systematically evaluated. Following PRISMA guidelines, we analyzed 8 independent cohorts (80 patients) treated with teclistamab or elranatamab. A random-effects model with Hartung-Knapp adjustment was employed to pool outcomes. The pooled hematologic overall response rate (ORR) was 91% (95% CI: 87%-93%), with a deep hematologic complete response (hCR) rate of 64% (95% CI: 42%-82%). Rapid organ recovery was a hallmark of treatment: the pooled cardiac and renal response rates reached 59% (95% CI: 32%-82%) and 34% (95% CI: 14%-62%), cytokine release syndrome (CRS) was frequent but manageable (60%; 95% CI: 53%-67%), while immune effector cell-associated neurotoxicity syndrome (ICANS) remained rare (7%). However, Grade ≥ 3 infections were observed in 25% (95% CI: 15%-40%) of patients, potentially associated with T-cell dysfunction and therapy-induced hypogammaglobulinemia. BCMA-directed BsAbs demonstrate potent hematologic efficacy in R/R AL, achieving deep and rapid light-chain clearance. This hematologic response translates into significant organ functional recovery. However, the high incidence of severe infections necessitates proactive antimicrobial prophylaxis, dose optimization, and immunoglobulin supplementation.
2026-06-18 | Teclistamab in relapsed/refractory light chain amyloidosis: A retrospective multicenter study by the German Society for Amyloid Diseases.
Systemic light chain (AL) amyloidosis is a rare, acquired protein misfolding disorder characterized by extracellular deposition of misfolded immunoglobulin light chain fibrils, resulting in organ damage. Treatment is based on anti-plasma cell regimens derived from multiple myeloma therapy. To date, no approved regimens exist for relapsed/refractory cases. This retrospective multicenter study, performed at 11 centers across Germany, evaluated the efficacy and tolerability of the treatment with teclistamab in 52 patients with relapsed/refractory AL amyloidosis. Hematologic response (≥very good partial response [VGPR]) was achieved in 81% of patients at Day 15, which increased to 95% at 3 months. Flow-minimal residual disease (MRD) was negative in 96% (23/24) of cases. Cardiac and renal responses (≥partial response [PR]) at 6 months were 65% and 78%, respectively. Cytokine release syndrome occurred in 37% of cases, with two classified as Grade 3 and none as Grade 4. Neutropenia Grade 3 or 4 occurred in 5/52 (10%) of patients. The 1-year overall survival was 83%, and the median overall survival was not reached after a median follow-up time of 8.8 months. Factors including difference between involved and non-involved free light chains (dFLC) ≥ 180 mg/L, N-terminal pro-brain natriuretic peptide (NTproBNP) ≥ 8500 pg/mL, glomerular filtration rate (GFR) < 20 mL/min/1.73 m2, and dialysis did not significantly impact overall survival. In total, nine patients deceased, six of whom deceased due to bacterial infections. Patients receiving immunoglobulin replacement therapy had a 2.01 lower risk of infections Grade 3 or 4 and a 6.14 lower risk of death. Our findings demonstrate the efficacy of teclistamab in a heavily diseased and pretreated cohort with AL amyloidosis and highlight the necessity of a concomitant immunoglobulin replacement therapy.
other
2025-09-27 | What Cardiologists Should Know About Amyloidosis.
Background: Cardiac amyloidosis (CA) is an increasingly recognized but historically underdiagnosed cause of restrictive cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). It results from the extracellular deposition of misfolded protein fibrils, most commonly transthyretin (ATTR) or immunoglobulin light chains (AL), leading to progressive myocardial dysfunction and multi-organ involvement. Objective: This review provides a comprehensive, cardiology-centered overview of cardiac amyloidosis, with an emphasis on early recognition, diagnostic strategies, subtype differentiation, and the evolving therapies. Content: We summarize the epidemiology, pathophysiology, and clinical manifestations of both ATTR and AL subtypes. Key diagnostic tools, including echocardiography, cardiac magnetic resonance imaging, bone scintigraphy, monoclonal protein screening, and endomyocardial biopsy, are reviewed in the context of a stepwise diagnostic approach. Special attention is given to clinical presentation, electrocardiographic and imaging "red flags," and to differentiating CA from mimickers such as hypertrophic cardiomyopathy, hypertension-induced left ventricular hypertrophy, and aortic stenosis. Staging systems are detailed, highlighting the prognostic role of cardiac biomarkers. Therapeutic strategies are explored, including subtype-specific regimens (e.g., daratumumab-based therapy for AL; tafamidis and gene silencers for ATTR), the judicious use of conventional heart failure medications, and emerging therapies such as CRISPR-based gene editing. Conclusions: Timely recognition and accurate diagnosis of cardiac amyloidosis are critical to improving outcomes. As diagnostic tools and disease-modifying therapies evolve rapidly, cardiologists must remain at the forefront of multidisciplinary care. A structured biomarker- and imaging-guided approach can enhance diagnostic yield, inform prognosis, and optimize patient-specific management.
2025-09-26 | Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy.
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare, multisystem, progressive, debilitating, and fatal disease characterized by tissue deposition of misfolded transthyretin (TTR) in peripheral nerves. Nexiguran ziclumeran (nex-z) is an investigational in vivo therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) that is designed to reduce serum TTR levels through selective inactivation of TTR in the liver. In this phase 1, open-label study, we administered one infusion of nex-z to patients with ATTRv-PN. Primary objectives included assessment of the safety and pharmacodynamics of nex-z. Secondary end points included changes in the familial amyloid polyneuropathy stage, polyneuropathy disability score, serum neurofilament light chain (NfL) level, modified body-mass index (modified BMI, defined as the conventional BMI [weight in kilograms divided by square of height in meters] multiplied by the albumin level in grams per liter), and modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment). A total of 36 patients received nex-z; the mean follow-up was 27 months. The mean percent change from baseline in the serum TTR level was -90% at day 28, which was sustained through month 24 (-92%). Treatment-related adverse events included transient infusion-related reactions (in 21 patients), decreased thyroxine level without hypothyroidism or elevated thyrotropin level (in 8), and headache (in 4). One participant died from cardiac amyloidosis, and one withdrew owing to progressive decline in motor function. Serious adverse events were reported in 11 patients. At month 24, the familial amyloid polyneuropathy stage and polyneuropathy disability score remained stable in 29 and 27 patients, respectively; improved in 2 and 5, respectively; and worsened in 2 and 2, respectively. The mean change in the serum NfL level was -9.0 pg per milliliter, and the change in the modified BMI was 24.7. The mean change from baseline in the mNIS+7 was -8.5. A single administration of nex-z in patients with ATTRv-PN was associated with rapid, deep, and durable reductions in serum TTR levels. The results support further investigation of nex-z to treat ATTRv-PN. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).
2025-05-28 | Cardiac Amyloidosis: A Narrative Review of Diagnostic Advances and Emerging Therapies.
Background/Objectives: Cardiac amyloidosis (CA) is an underdiagnosed and potentially life-threatening infiltrative cardiomyopathy characterized by the extracellular deposition of misfolded amyloid fibrils in cardiac tissue. It is most commonly associated with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis, either hereditary or wild-type. The disease often presents with non-specific symptoms, leading to delayed diagnosis and treatment. This study aims to provide a comprehensive overview of the pathophysiology, diagnostic strategies, and current therapeutic approaches for cardiac amyloidosis, with a focus on improving early detection and clinical outcomes. Methods: A narrative review was conducted using databases such as PubMed and Scopus, covering the period from September 2016 to March 2025. Keywords such as "cardiac amyloidosis", "cardiac amyloidosis from transthyretin", "cardiomyopathy", "transthyretin", "immunoglobulin light-chain amyloidosis", and "familial amyloidosis" were used. Relevant clinical trials and guideline-based management recommendations were also included. Results: This review highlights that non-invasive imaging modalities and serum biomarker analyses are key to reducing diagnostic delays. New therapeutic developments, including gene-editing technologies and RNA-based therapies, show promise in early trials. Multidisciplinary management and increased awareness are crucial for timely diagnosis and treatment optimization. Conclusions: The early recognition of cardiac amyloidosis remains a major clinical challenge. Advances in non-invasive diagnostics and emerging disease-modifying therapies are transforming the prognosis of affected patients. Continued research and heightened clinical suspicion are essential to improve outcomes in this complex and heterogeneous disease.
2024-08-19 | Current Therapies and Future Horizons in Cardiac Amyloidosis Treatment.
Cardiac amyloidosis (CA) is a condition characterized by misfolding and extracellular deposition of proteins, leading to organ dysfunction. While numerous forms of CA exist, two subtypes dominate clinical prevalence: Transthyretin amyloid (ATTR) and immunoglobulin light chain amyloid. The current scientific landscape reflects the urgency to advance therapeutic interventions with over 100 ongoing clinical trials. Heart failure treatment is affected by CA phenotype with poor tolerance of otherwise frequently used medications. Treating comorbidities including atrial fibrillation and valvular disease remains a challenge in CA, driven by technical difficulties and uncertain outcomes. Tafamidis is the first ATTR-stabilizer approved with a rapidly growing rate of clinical use. In parallel, various new therapeutic classes are in late-stage clinical trials including silencers, antibodies and genetic therapy. Managing CA is a critical challenge for future heart failure care. This review delineates the current standard-of-care and scientific landscape of CA therapy.
2024-04-01 | 381 BiP knockdown decreases antibody production in malignant and non-malignant plasma cells
OBJECTIVES/GOALS: Numerous diseases, including AL amyloidosis, are due to expression of aberrant antibodies. Significant effort has gone into plasma cell toxic therapies with varying degrees of success, but no therapies preventing antibody synthesis have been developed. The goal of this study is to assess BiP targeting to prevent antibody secretion in plasma cells. METHODS/STUDY POPULATION: Using 4 multiple myeloma cell lines (KMS11, RPMI8226, ANBL-6, U266), we knocked down BiP expression with RnaseH dependent siRNA or subA toxin, a bacterial toxin that specifically cleaves BiP, and measured changes in unfolded protein and intracellular light chains by flow cytometry during drug induced ER stress created by the intracellular calcium depleting agent thapsigargin. BiP is the master regulator of the unfolded protein response (UPR), an ER stress pathway important for protein folding. BiP is also an ER resident protein folding chaperone important for proper antibody folding. We hypothesized that BiP downregulation will lead to decreased folded antibody in the cell, increased unfolded antibody and constitutive activation of the UPR. RESULTS/ANTICIPATED RESULTS: 1 to 4 hours after treatment with thapsigargin plus siRNA against BiP, levels of BiP are significantly decreased. The levels of intracellular light chains decrease, and the level of unfolded protein within the cells increases dramatically. Interestingly, in alignment with the UPR literature, 24 hours post treatment, these levels have normalized again in surviving cells. SubA treatment increased BiP expression by 4 hours, contrary to our hypothesis, and minimally increased unfolded proteins and minimally decreased intracellular light chains. We expect that further functional testing of antibody secretion by ELIspot assays will show decreased secretion of antibody with BiP siRNA treatment. Combination therapies with other UPR stressing agents may act synergistically to affect antibody production. DISCUSSION/SIGNIFICANCE: BiP knockdown reduces antibodies and boosts unfolded proteins. SubA toxin ineffectiveness likely stems from increased BiP due to feedback loops. Combining anti-BiP treatments with UPR stressing drugs like bortezomib may halt antibody synthesis and induce cell death. These findings support BiP as a viable drug target for antibody-related diseases.
small molecules
2026-08-13 | Amyloidosis and Thoracic Aortic Disease: A Scoping Review.
Background and Objectives: Amyloidosis is a systemic disorder characterized by extracellular deposition of misfolded protein fibrils, most commonly light-chain (AL) or transthyretin-derived (ATTR) ones. Cardiac involvement is well recognized, but large-vessel complications, including thoracic aortic aneurysms (TAA) and dissections, are rare and under-reported. The aim of this review article is to provide insights into pathophysiology, clinical diagnosis and the therapeutic opportunities in amyloidosis-related thoracic aortic diseases. Methods and Materials: The PRISMA Extension for Scoping Reviews (PRISMA-ScR) Guidelines were followed. An extensive search of the available literature in the English language, published between 1 January 2000, and 31 December 2025, in three large-scale scientific databases was undertaken by two independent reviewers. The terms "amyloidosis", "thoracic aorta", "thoracic aortic aneurysm", "aortic dissection", and "aortopathy" were used both as specific items, as well as in MeSH Terms. Studies reporting on the pathophysiology, diagnosis, clinical manifestations, treatment options and prognosis of amyloid deposition on the thoracic aorta were included in the review. Because of the nature of the existing literature, only a narrative review was possible. Results: Twenty-nine studies were included. Owing to the rarity of reporting, data was derived mainly from case reports and series, as well as autopsy studies. Amyloid infiltration of the aortic wall has been associated with medial architectural disruption, degeneration of elastic fibers, impairment of vasa vasorum perfusion, and arterial stiffness, all of which could contribute to aneurysmal dilation and aortic lesions. Amyloidosis management combines targeted anti-plasma cell therapy with supportive care. In AL amyloidosis, melphalan-dexamethasone (MDex) was historically standard, but regimens such as cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and bortezomib, melphalan, and dexamethasone (BMDex) achieve higher complete response rates. Immunotherapy with Daratumumab has shown high overall and complete response rates. Fibril-directed approaches, including doxycycline and epigallocatechin gallate, and monoclonal antibodies, are under evaluation. Acute management of large-vessel manifestations follows conventional protocols, but prognosis is often dominated by underlying cardiac and systemic involvement. Conclusions: Management of thoracic aortic involvement follows standard imaging surveillance and surgical criteria, though operative risk is increased. Multidisciplinary care, early recognition, and individualized risk stratification are essential to improve outcomes, particularly given frequent cardiac involvement.
2026-08-08 | Limited duration of dexamethasone in newly diagnosed AL amyloidosis: impact on response, toxicity, and survival.
Systemic light chain amyloidosis (AL) is a life-threatening disease in which dexamethasone (Dex) is a core therapy but is limited by cumulative toxicity. The optimal duration of Dex, particularly in the era of daratumumab (Dara)-based regimens, is uncertain. We retrospectively analyzed 216 newly diagnosed AL amyloidosis patients (2017-2023). Dex exposure was categorized as limited (≤3 months) or prolonged (>3 months) using restricted cubic spline-derived associations with hematologic response kinetics. Outcomes included hematologic and organ response, toxicity, and overall survival. Median Dex duration was 5.5 months and was similar by Dara use. Overall response rates exceeded 90% at 6 months in both Dex groups. Limited Dex was associated with higher rates of early deep hematologic response (VGPR or better 77.5 vs 56.5%, p = 0.001; CR 42.2 vs 19.4%, p < 0.001), reflecting faster response kinetics, while overall response rates were similar. Among patients receiving limited Dex, Dara was associated with higher 6-month CR rates (66.7 vs 30.4%, p < 0.001) and increased likelihood of achieving CR in multivariable analysis (HR 4.38, 95% CI 2.44-7.85; p < 0.001). Organ responses were similar between groups. Dex-related toxicities increased after 6 months, and hospitalization was associated with worse survival. Limiting Dex exposure was associated with preserved efficacy and reduced toxicity. Prolonged Dex was associated with increased toxicity without improving overall hematologic or organ outcomes, supporting limited Dex duration in frontline AL amyloidosis therapy.
2026-08-08 | AL Cardiac Amyloidosis in Resource-Limited Settings: Diagnostic Challenges and Therapeutic Gaps.
Amyloid light chain (AL) cardiac amyloidosis remains a diagnostic challenge in resource-limited settings. We present 3 cases with varying heart failure presentations, all demonstrating concentric left ventricular hypertrophy with characteristic apical sparing strain pattern on echocardiography. Serum free light chains were consistently abnormal, though immunofixation was negative in 2 patients. Traditional screening biopsies were negative in 2 cases, requiring endomyocardial biopsy for diagnosis. Mass spectrometry for amyloid typing was unavailable; immunofluorescence performed in 1 patient confirmed lambda light chain deposition. All patients received CyBorD-based therapy; 1 patient additionally accessed daratumumab abroad and showed marked improvement, while another died within 6 months on CyBorD alone. These cases highlight the heterogeneous presentation of presumed AL amyloidosis and underscore how diagnostic barriers contribute to delayed diagnosis and more advanced disease at presentation, emphasizing the urgent need for improved diagnostic capabilities and therapeutic accessibility in resource-constrained settings.
2026-08-03 | [Improvement of chylothorax after lymphangiography in AL amyloidosis].
A 74-year-old man presented with leg edema and was found to have nephrotic-range proteinuria. Renal biopsy revealed AL amyloidosis. Subsequent bone marrow examination demonstrated an increase in monoclonal plasma cells accounting for 13% of nucleated cells. Right-sided pleural effusion developed and was confirmed to be chylothorax. Although treatment with daratumumab, lenalidomide, and dexamethasone (DLd regimen) was initiated, the pleural effusion continued to increase. Lymphangiography using ethiodized oil identified a leakage point in the anterior mediastinum. A chest drain was inserted on the following day, and approximately 4 l of chylous fluid was drained. The tube was removed one week later, and pleural effusion did not recur thereafter. Although a hematologic response was achieved, the nephrotic syndrome persisted, and the patient ultimately died. Chylothorax associated with AL amyloidosis is rare and difficult to treat. This case suggests that lymphangiography using ethiodized oil may be both diagnostic and therapeutic.
2026-07-30 | Preventive Effects of Non-sedating and Sedating Histamine H1 Receptor Antagonists Premedication for Subcutaneous Daratumumab-Associated Infusion-Related Reactions: A Prospective Observational Study.
The optimal choice between sedating histamine H1 antagonists (sAHs) and non-sedating histamine H1 antagonists (nsAHs) for preventing infusion-related reactions (IRRs) during daratumumab subcutaneous (DARA-SC) therapy remains unclear. Here, we aimed to compare the efficacy and safety of nsAH and sAH as premedication for DARA-SC therapy. Patients with multiple myeloma or light-chain amyloidosis who received DARA-SC therapy at eight hospitals were enrolled in this prospective, multicenter, observational study. Patients were categorized into nsAH and sAH groups based on their premedication. IRRs and drowsiness were assessed using patient-reported questionnaires, including the Stanford Sleepiness Scale (SSS) and the Japanese Epworth Sleepiness Scale (JESS), at baseline, post-administration (Q2), and before bedtime (Q3). Overall, 104 patients (nsAH, n = 49; sAH, n = 55) were analyzed. No significant differences were observed in the IRR incidence between the nsAH and sAH groups at Q2 (8.2 vs. 9.1%) or Q3 (13 vs. 17%). Conversely, the incidence of new-onset drowsiness at Q2 was significantly lower in the nsAH group (13%) than in the sAH group (32%, p < 0.05). Additionally, the increase in SSS from baseline to Q2 was significantly lower in the nsAH group than in the sAH group (p < 0.05). No significant differences were observed in JESS scores. Thus, nsAH was associated with reduced early post-administration drowsiness and there were no statistically significant differences in IRR preventive effects compared to that for sAH, suggesting that nsAH may reduce sedation without a significant increase in the incidence of IRRs; however, these hypothesis-generating findings warrant verification through future prospective comparative trials.
proteins
2026-06-29 | Siphoviridae phage tails co-enrich with ex vivo amyloids.
Bacteriophages are ubiquitous in the environment and are part of the natural human microbiome. Despite their abundance, the role of the human phagome in health and disease remains poorly understood. Here, we identify phage tails in ex vivo amyloid extracts from patients with lysozyme amyloidosis (ALys) and light-chain amyloidosis (AL). Using cryo-EM analysis of the ALys dataset, automated model building, and database searches, we assigned the observed tubular assemblies to a phage tail tube protein (TTP). Although we cannot fully rule out the possibility of contamination, the presence of phage tails raises the question of whether they bind to and are co-purified with amyloid fibrils. These structures may provide further insight into the potential relationship between phage-derived assemblies and amyloid remodeling, with possible implications for future therapeutic strategies in human amyloidosis.
2026-06-22 | Multifaceted effects of N-glycosylation on amyloidogenic κ light chains in AL amyloidosis.
Light chain (LC) amyloidosis (AL) is a fatal disorder caused by extracellular aggregation of monoclonal immunoglobulin LCs. While both λ and κ isotypes can be involved, κ-LCs account for only ∼20% of cases, and their aggregation mechanisms remain less understood. Recent evidence suggests that N-glycosylation influences κ-LC aggregation and is strongly linked to AL amyloidosis. To investigate this, we examined patient-derived κ-LCs in both glycosylated and unglycosylated forms. Mass spectrometry confirmed the presence of complex-type N-glycans. Biophysical analyses showed that glycosylation enhances structural compactness, stabilizes the native structure, and promotes cooperative unfolding. Glycosylated κ-LCs also exhibited reduced conformational dynamics. Functionally, N-glycosylation significantly improved LC secretion efficiency and extracellular stability. These findings suggest that N-glycosylation acts as a protective factor against amyloid formation and enhances LC accumulation outside the cell. Overall, our study highlights the multifaceted and context-dependent role of N-glycosylation in modulating κ-LC behavior, with important implications in AL pathogenesis.
2026-05-21 | A CDR1 aggregation hotspot controls unfolding kinetics and multimolecular aggregation in IGLV2 light chains.
Immunoglobulin light chains (LCs) exhibit diverse aggregation behaviours that depend sensitively on sequence composition and intermolecular interactions. Understanding how specific residues modulate aggregation kinetics remains a key challenge in elucidating the molecular basis of light-chain amyloidosis. Here, we investigate sequence-dependent aggregation using recombinant λ LCs derived from the IGLV2 gene family. Comparison of two closely related LCs differing by only 16 amino acids revealed striking differences in aggregation behaviour under thermal stress. Bioinformatic analysis identified an additional aggregation-prone segment in the CDR1 region of the aggregation-prone M10 variant, associated with residues Ser33 and Tyr34. Rational substitution of these residues (S33D/Y34S) markedly reduced aggregation while leaving the thermal transition temperature largely unchanged (∼53 °C). Differential scanning calorimetry revealed that the wild-type M10 LC unfolds with a significantly lower apparent activation energy (∼290 kJ/mol) compared with the non-aggregating H9 (∼605 kJ/mol) and the stabilised double mutant (∼560 kJ/mol), indicating reduced kinetic stability. Aggregation of unfolded species showed much weaker temperature dependence (Ea ≈ 10-70 kJ/mol) and exhibited strong concentration dependence consistent with a multimolecular association process. Additional experiments suggest that aromatic interactions involving Tyr34 contribute to the stabilisation of intermolecular assemblies. Together, these results establish a quantitative link between local sequence variation in the CDR1 region, kinetic stability of the LC fold, and aggregation propensity, highlighting how targeted mutations can modulate aggregation behaviour in immunoglobulin light chains.
2026-04-08 | Preventing Pathogenic Dimerization in a Misfolded Antibody Light Chain through the Design of an Inhibitory Peptide.
Immunoglobulin light chain (AL) amyloidosis is the most common form of systemic amyloidosis. The disease correlates with the formation of insoluble aggregates mostly composed of patient-specific antibody light chains, whose hypervariable regions make each case unique and highlight the need for personalized therapeutics. In this study, we focused on a pathogenic homodimer we previously obtained from a patient-derived light chain. By analyzing the dynamics and the interface of this dimer, we identified a peptide with potential inhibitory activity. The peptide was then refined using a computational mutagenesis protocol that iteratively improved its sequence to maximize complementarity with the protein interface, taking into account shape, electrostatics, and hydropathy. The resulting optimized peptide is found to bind the monomer with a binding affinity comparable to that of the full pathogenic interface. These results suggest that the designed peptide could act as an effective antagonist of the pathogenic dimer, and demonstrate that our computational strategy could provide a general framework for designing patient-specific inhibitory peptides against aggregation-prone proteins.
2025-06-02 | The utility of intravenous immunoglobulin infection prophylaxis in patients on anti-CD38 therapies.
BackgroundAnti-CD38 directed therapies have emerged as targeted treatments for multiple myeloma (MM) and light chain (AL) amyloidosis. Intravenous immunoglobulin (IVIG) supplementation has been shown to reduce the risk of bacterial infections by 39% in patients with MM receiving anti-CD38 therapies, with a 72% reduction in grade 3-4 infections. However, there is currently no universal guidance on the optimal population in whom to initiate IVIG prophylaxis to prevent these infectious complications.MethodsThis study was a retrospective, single-centered chart review of eligible patients treated at Yale New Haven Health System (YNHHS) from 2016-2022. Eligible patients included adults with MM or AL amyloidosis treated with an anti-CD38 based regimen. The primary outcome was to compare the rate of pneumonia in patients who have received IVIG as compared to patients who have not. The secondary outcome was to identify the immunoglobulin G (IgG) level associated with an increased risk of pneumonia.ResultsRates of pneumonia were found to be higher within the population receiving IVIG as compared to those not receiving IVIG (29.55% vs. 15.41%, p = 0.05). There were no significant differences in the subgroup analyses including line of therapy, anti-CD38 agent, diagnosis, and IgG disease involvement. There was also no significant correlation demonstrated between baseline IgG level and the occurrence of pneumonia (β1 -0.0001, p = 0.37).ConclusionsIVIG supplementation in patients receiving anti-CD38 directed therapy did not significantly reduce the incidence of pneumonia. Given the lack of benefit with IVIG supplementation, careful consideration must be given prior to administration to limit unnecessary utilization.
cell therapies
2026-07-21 | Efficacy and Safety of BCMA-Targeted Therapies in Relapsed or Refractory AL Amyloidosis: A Descriptive Pooled Analysis.
B-cell maturation antigen (BCMA)-targeted therapies have emerged as promising treatment options for patients with relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. However, comprehensive data on their efficacy and safety remain limited. We conducted a systematic descriptive pooled analysis of published studies reporting outcomes of BCMA-directed therapies including chimeric antigen receptor T-cell (CAR-T) therapies, bispecific antibodies (BsAbs), and antibody-drug conjugate (ADC). The analysis included 256 patients. CAR-T therapy was administered to 89 patients (35%), BsAbs to 82 patients (32%), and ADCs to 85 patients (33%). The pooled overall response rate (ORR) was 83%, with CAR-T demonstrating 92% ORR, BsAbs 89%, and ADCs 68%. Deep hematologic responses (≥VGPR) were achieved in approximately 70% of CAR-T and BsAb recipients and 64% of ADC recipients. Minimal residual disease negativity was documented in 75% of evaluable CAR-T patients and in 86% evaluable BsAb patients with reported data. Organ responses were observed in 30% of evaluable patients, with cardiac responses in 41%. Cytokine release syndrome occurred in 74% of CAR-T and 49% of BsAb patients, predominantly grade 1-2. Grade ≥3 CRS was rare (9% CAR-T, 1% BsAb). Ocular toxicity was the predominant adverse event in ADC recipients (84% any grade, 29% grade ≥3). Grade ≥3 infections occurred in 13% of CAR-T, 20% of BsAb, and 6% of ADC patients. BCMA-targeted therapies result in high response rates with manageable safety profiles in heavily pretreated AL amyloidosis patients, supporting continued investigation and clinical application of these approaches.
2026-06-23 | Autologous stem cell transplantation for AL amyloidosis: a multicenter summary of outcomes 2010-2020.
The role of autologous stem cell transplantation (ASCT) is central in AL amyloidosis and continues to be defined in the era of newer therapies. To evaluate contemporary patient selection, practice patterns, and outcomes, we conducted a retrospective, multicenter study across nine tertiary referral centers, including 1047 patients with AL amyloidosis who underwent ASCT between 2010 and 2020. Most patients (67.9%) received full-dose melphalan conditioning, and 66.5% received pre-ASCT induction therapy, predominantly proteasome inhibitor-based regimens. Day-100 all-cause mortality was 3.0%, representing a substantial improvement compared with historical cohorts. Post-ASCT hematological responses were satisfactory in 75.4% of patients. Among patients with paired assessments, ASCT deepened responses in 56.3% who had not achieved a complete response with induction therapy. With a median follow-up of 5.1 years, the median overall survival was 6.3 years. Independent predictors of inferior survival included age ≥60 years, bone marrow plasma cells ≥20%, pre-ASCT dFLC ≥40 mg/L, elevated cardiac biomarkers, lambda-restricted disease, reduced eGFR and reduced-dose conditioning. In this contemporary cohort, ASCT for AL amyloidosis demonstrated low early mortality, high rates of deep hematologic response, and durable survival in carefully selected patients. These findings support its role as an effective consolidative strategy, while its optimal positioning alongside emerging therapies requires further study.
2026-05-01 | A rare case of renal AHL amyloidosis with marked complement deposition: clinicopathologic and proteomic findings.
Amyloidosis comprises a heterogeneous group of diseases characterized by extracellular deposition of β-pleated-sheet fibrillar proteins that cause progressive organ dysfunction. Among immunoglobulin-related amyloidosis, combined heavy- and light-chain (AHL) amyloidosis is extremely rare, which accounts for approximately 7%. Several studies have demonstrated that complement components can be detected in renal amyloidosis. We report a rare case of renal AHL amyloidosis with marked complement deposition with clinicopathologic and proteomic insights. A 76-year-old woman with a five-year history of microscopic hematuria developed mild renal dysfunction (serum creatinine 1.05 mg/dL) and proteinuria (0.95 g/day). Physical and serologic evaluations showed no evidence of systemic amyloidosis or autoimmune disease. Serum and urine immunofixation detected an IgG-κ M-protein, and bone marrow findings were consistent with monoclonal gammopathy of undetermined significance. Kidney biopsy demonstrated Congo red-positive fibrillar deposits with IgG1, κ, and complement (C3/C1q) staining. Electron microscopy revealed non-branching fibrils measuring 8 to 12 nm in diameter. Because marked complement deposition was observed, fibrillary glomerulonephritis (FGN) was considered in the differential diagnosis. However, negative Dna J heat-shock protein family B member 9 immunostaining raised suspicion for amyloidosis. Mass spectrometry identified IgG1 heavy and κ light chains together with serum amyloid P and apolipoprotein E, confirming IgG1-κ-type AHL amyloidosis. This case illustrates a presentation of AHL amyloidosis with marked complement deposition. Recent study reveals that complement components can be detected in a subset of amyloidosis cases. These features can complicate the differential diagnosis from FGN and highlight the importance of an integrated diagnostic approach combining histopathology, immunostaining, and proteomic analysis. Furthermore, clone-directed therapy targeting the pathogenic plasma cell clone may represent a rational therapeutic strategy for monoclonal immunoglobulin-associated renal disease.
2026-02-05 | Improvement in Cardiac Magnetic Resonance Parameters in Patients With Cardiac Light-Chain Amyloidosis Receiving Anticlonal Cell Therapy.
We sought to evaluate the pattern of changes in cardiac magnetic resonance parameters among light-chain (AL) cardiac amyloidosis patients receiving anticlonal therapy. This study included 35 consecutive patients with AL cardiac amyloidosis (AL CA) from a single amyloidosis center, surviving at least 1 year after diagnosis and undergoing 3T CMR at diagnosis and at 12-months follow-up. Structural, functional parameters, native T1, T2, myocardial and spleen extracellular volume (ECV), and peak left atrial strain (PALS) were recorded. Hematologic response was assessed per current criteria. Mean age was 64.1 years, 57% males and per Mayo staging system 10% were stage I, 32% stage II, and 58% stage III. During follow-up, 54.3% achieved complete hematologic response (CR), 34.3% very good partial response, and 11.4% partial response. Significant changes at 12-month landmark included a reduction in native T1 (1420 ms vs. 1393 ms, P = .001), ECV (46% vs. 43%, P = .004), left ventricular maximum wall thickness (15 mm vs. 13 mm, P = .02), and an increase in stroke volume (76 mL vs. 85 mL, P = .016). Patients with complete hematologic or cardiac response demonstrated improvements in T1 native and ECV. In a subset of n = 12 patients with a repeated follow-up CMR study at a median of 31.2 ± 5.04 months after treatment initiation, a trend towards further reduction in T1 and ECV was noted. In AL-CA patients treated with anticlonal therapy, significant improvement in CMR parameters, correlate with hematologic and organ response and suggest potential cardiac amyloid regression and functional improvement.
2025-12-08 | Up-to-date review on heart transplantation and other advanced heart failure therapies in cardiac amyloidosis patients.
Cardiac amyloidosis (CA) can result in a restrictive cardiomyopathy, and heart transplantation (HT) remains the gold standard treatment for patients with end-stage heart failure secondary to amyloid cardiomyopathy. Although HT was historically contraindicated due to inferior outcomes, survival following HT in patients with CA has significantly improved over recent decades; and outcomes are now similar to those of patients undergoing HT for non-amyloid indications. This improvement has been driven largely by advances in screening for appropriate patient selection and improvement in therapeutic strategies for both immunoglobulin light-chain (AL) and transthyretin (ATTR) amyloidosis. Future directions in HT for CA will hinge on continued optimization of patient selection and refining post-transplant management of extracardiac manifestations.
antibodies
2026-08-10 | IgM Pleural Amyloidosis Diagnosed by Pleural Effusion Cell Block: A Case Report.
Immunoglobulin light chain (AL) amyloidosis is characterized by the systemic deposition of light-chain-derived amyloids. Immunoglobulin M (IgM)-associated AL amyloidosis is extremely rare and clinically distinct. A 70-year-old man presented with dyspnea, bilateral pleural effusion, and mediastinal lymphadenopathy on computed tomography (CT). Amyloid was detected in a pleural effusion cell block and confirmed via an axillary lymph node biopsy. Serum studies and bone marrow findings supported IgM-λ AL amyloidosis associated with Waldenström macroglobulinemia/lymphoplasmacytic lymphoma. First-line therapy failed, but second-line therapy reduced pleural effusion, avoiding thoracentesis for one year. A pleural effusion cell block analysis enabled rapid diagnosis with minimally invasive exploration.
2026-07-20 | Histopathological improvement in kidney AL amyloid deposits following daratumumab-based chemotherapy and autologous peripheral blood stem cell transplantation: a case report.
AL amyloidosis is characterized by extracellular deposition of immunoglobulin light-chain fibrils, frequently leading to kidney involvement and progressive organ dysfunction. We report a case of kidney AL amyloidosis secondary to multiple myeloma in which daratumumab-based chemotherapy combined with autologous peripheral blood stem cell transplantation resulted in marked improvement, as confirmed by sequential kidney biopsy. The initial biopsy revealed vascular-dominant amyloid deposition, whereas the second biopsy obtained 2 years later demonstrated a marked reduction in amyloid burden, particularly within the vascular compartments. This histopathological improvement corresponded with hematologic remission and stabilization of kidney function. The observed reduction in tissue amyloid deposits was presumed to result from suppression of amyloidogenic light chains, leading to inhibition of new fibril formation and subsequent tissue remodeling. Our findings provide direct pathological evidence that daratumumab-based combination therapy, through immune-mediated plasma cell depletion, may indirectly promote the regression of amyloid deposits and contribute to functional recovery.
2026-07-09 | Systemic light chain and transthyretin amyloidosis-treatment advancements and future directions.
Once rapidly fatal, neglected, and orphan diseases without approved therapeutic options, systemic amyloidoses are now highly treatable. Basic scientific discoveries regarding the molecular mechanisms of transthyretin misfolding and aggregation have driven the development of drugs for the treatment of transthyretin (ATTR) amyloidosis, with six novel therapies approved since 2018. The combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone was approved for the treatment of light chain (AL) amyloidosis in 2021. Since then, highly effective immunotherapies, such as bispecific T-cell engagers, have been tested in clinical trials in patients with relapsed AL amyloidosis, with unprecedented efficacy. Thus, suspicion of systemic amyloidosis should be raised early in individuals with a suggestive clinical presentation, followed by rapid tissue diagnosis, with appropriate protein typing and prompt commencement of active therapy. These rapid and exciting therapeutic advancements set the stage for this Review on the epidemiology, pathophysiology, and diagnosis of systemic amyloidosis. Through the lens of the molecular mechanisms underlying amyloidosis pathogenesis, we will focus on approved and investigational therapies. We also discuss future directions and challenges concerning a cure for patients with AL or ATTR amyloidosis.
2026-06-18 | Efficacy and safety of BCMA-directed bispecific antibodies in relapsed and/or refractory systemic AL amyloidosis: A systematic review and meta-analysis.
Patients with relapsed/refractory (R/R) systemic light chain (AL) amyloidosis, particularly after daratumumab failure, face limited treatment options and challenging outcomes. B-cell maturation antigen (BCMA)-directed bispecific antibodies (BsAbs) have emerged as a potent strategy in multiple myeloma, yet their collective performance in AL amyloidosis remains to be systematically evaluated. Following PRISMA guidelines, we analyzed 8 independent cohorts (80 patients) treated with teclistamab or elranatamab. A random-effects model with Hartung-Knapp adjustment was employed to pool outcomes. The pooled hematologic overall response rate (ORR) was 91% (95% CI: 87%-93%), with a deep hematologic complete response (hCR) rate of 64% (95% CI: 42%-82%). Rapid organ recovery was a hallmark of treatment: the pooled cardiac and renal response rates reached 59% (95% CI: 32%-82%) and 34% (95% CI: 14%-62%), cytokine release syndrome (CRS) was frequent but manageable (60%; 95% CI: 53%-67%), while immune effector cell-associated neurotoxicity syndrome (ICANS) remained rare (7%). However, Grade ≥ 3 infections were observed in 25% (95% CI: 15%-40%) of patients, potentially associated with T-cell dysfunction and therapy-induced hypogammaglobulinemia. BCMA-directed BsAbs demonstrate potent hematologic efficacy in R/R AL, achieving deep and rapid light-chain clearance. This hematologic response translates into significant organ functional recovery. However, the high incidence of severe infections necessitates proactive antimicrobial prophylaxis, dose optimization, and immunoglobulin supplementation.
2026-06-18 | Teclistamab in relapsed/refractory light chain amyloidosis: A retrospective multicenter study by the German Society for Amyloid Diseases.
Systemic light chain (AL) amyloidosis is a rare, acquired protein misfolding disorder characterized by extracellular deposition of misfolded immunoglobulin light chain fibrils, resulting in organ damage. Treatment is based on anti-plasma cell regimens derived from multiple myeloma therapy. To date, no approved regimens exist for relapsed/refractory cases. This retrospective multicenter study, performed at 11 centers across Germany, evaluated the efficacy and tolerability of the treatment with teclistamab in 52 patients with relapsed/refractory AL amyloidosis. Hematologic response (≥very good partial response [VGPR]) was achieved in 81% of patients at Day 15, which increased to 95% at 3 months. Flow-minimal residual disease (MRD) was negative in 96% (23/24) of cases. Cardiac and renal responses (≥partial response [PR]) at 6 months were 65% and 78%, respectively. Cytokine release syndrome occurred in 37% of cases, with two classified as Grade 3 and none as Grade 4. Neutropenia Grade 3 or 4 occurred in 5/52 (10%) of patients. The 1-year overall survival was 83%, and the median overall survival was not reached after a median follow-up time of 8.8 months. Factors including difference between involved and non-involved free light chains (dFLC) ≥ 180 mg/L, N-terminal pro-brain natriuretic peptide (NTproBNP) ≥ 8500 pg/mL, glomerular filtration rate (GFR) < 20 mL/min/1.73 m2, and dialysis did not significantly impact overall survival. In total, nine patients deceased, six of whom deceased due to bacterial infections. Patients receiving immunoglobulin replacement therapy had a 2.01 lower risk of infections Grade 3 or 4 and a 6.14 lower risk of death. Our findings demonstrate the efficacy of teclistamab in a heavily diseased and pretreated cohort with AL amyloidosis and highlight the necessity of a concomitant immunoglobulin replacement therapy.
other
2025-09-27 | What Cardiologists Should Know About Amyloidosis.
Background: Cardiac amyloidosis (CA) is an increasingly recognized but historically underdiagnosed cause of restrictive cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). It results from the extracellular deposition of misfolded protein fibrils, most commonly transthyretin (ATTR) or immunoglobulin light chains (AL), leading to progressive myocardial dysfunction and multi-organ involvement. Objective: This review provides a comprehensive, cardiology-centered overview of cardiac amyloidosis, with an emphasis on early recognition, diagnostic strategies, subtype differentiation, and the evolving therapies. Content: We summarize the epidemiology, pathophysiology, and clinical manifestations of both ATTR and AL subtypes. Key diagnostic tools, including echocardiography, cardiac magnetic resonance imaging, bone scintigraphy, monoclonal protein screening, and endomyocardial biopsy, are reviewed in the context of a stepwise diagnostic approach. Special attention is given to clinical presentation, electrocardiographic and imaging "red flags," and to differentiating CA from mimickers such as hypertrophic cardiomyopathy, hypertension-induced left ventricular hypertrophy, and aortic stenosis. Staging systems are detailed, highlighting the prognostic role of cardiac biomarkers. Therapeutic strategies are explored, including subtype-specific regimens (e.g., daratumumab-based therapy for AL; tafamidis and gene silencers for ATTR), the judicious use of conventional heart failure medications, and emerging therapies such as CRISPR-based gene editing. Conclusions: Timely recognition and accurate diagnosis of cardiac amyloidosis are critical to improving outcomes. As diagnostic tools and disease-modifying therapies evolve rapidly, cardiologists must remain at the forefront of multidisciplinary care. A structured biomarker- and imaging-guided approach can enhance diagnostic yield, inform prognosis, and optimize patient-specific management.
2025-09-26 | Nexiguran Ziclumeran Gene Editing in Hereditary ATTR with Polyneuropathy.
Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a rare, multisystem, progressive, debilitating, and fatal disease characterized by tissue deposition of misfolded transthyretin (TTR) in peripheral nerves. Nexiguran ziclumeran (nex-z) is an investigational in vivo therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) that is designed to reduce serum TTR levels through selective inactivation of TTR in the liver. In this phase 1, open-label study, we administered one infusion of nex-z to patients with ATTRv-PN. Primary objectives included assessment of the safety and pharmacodynamics of nex-z. Secondary end points included changes in the familial amyloid polyneuropathy stage, polyneuropathy disability score, serum neurofilament light chain (NfL) level, modified body-mass index (modified BMI, defined as the conventional BMI [weight in kilograms divided by square of height in meters] multiplied by the albumin level in grams per liter), and modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment). A total of 36 patients received nex-z; the mean follow-up was 27 months. The mean percent change from baseline in the serum TTR level was -90% at day 28, which was sustained through month 24 (-92%). Treatment-related adverse events included transient infusion-related reactions (in 21 patients), decreased thyroxine level without hypothyroidism or elevated thyrotropin level (in 8), and headache (in 4). One participant died from cardiac amyloidosis, and one withdrew owing to progressive decline in motor function. Serious adverse events were reported in 11 patients. At month 24, the familial amyloid polyneuropathy stage and polyneuropathy disability score remained stable in 29 and 27 patients, respectively; improved in 2 and 5, respectively; and worsened in 2 and 2, respectively. The mean change in the serum NfL level was -9.0 pg per milliliter, and the change in the modified BMI was 24.7. The mean change from baseline in the mNIS+7 was -8.5. A single administration of nex-z in patients with ATTRv-PN was associated with rapid, deep, and durable reductions in serum TTR levels. The results support further investigation of nex-z to treat ATTRv-PN. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).
2025-05-28 | Cardiac Amyloidosis: A Narrative Review of Diagnostic Advances and Emerging Therapies.
Background/Objectives: Cardiac amyloidosis (CA) is an underdiagnosed and potentially life-threatening infiltrative cardiomyopathy characterized by the extracellular deposition of misfolded amyloid fibrils in cardiac tissue. It is most commonly associated with light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis, either hereditary or wild-type. The disease often presents with non-specific symptoms, leading to delayed diagnosis and treatment. This study aims to provide a comprehensive overview of the pathophysiology, diagnostic strategies, and current therapeutic approaches for cardiac amyloidosis, with a focus on improving early detection and clinical outcomes. Methods: A narrative review was conducted using databases such as PubMed and Scopus, covering the period from September 2016 to March 2025. Keywords such as "cardiac amyloidosis", "cardiac amyloidosis from transthyretin", "cardiomyopathy", "transthyretin", "immunoglobulin light-chain amyloidosis", and "familial amyloidosis" were used. Relevant clinical trials and guideline-based management recommendations were also included. Results: This review highlights that non-invasive imaging modalities and serum biomarker analyses are key to reducing diagnostic delays. New therapeutic developments, including gene-editing technologies and RNA-based therapies, show promise in early trials. Multidisciplinary management and increased awareness are crucial for timely diagnosis and treatment optimization. Conclusions: The early recognition of cardiac amyloidosis remains a major clinical challenge. Advances in non-invasive diagnostics and emerging disease-modifying therapies are transforming the prognosis of affected patients. Continued research and heightened clinical suspicion are essential to improve outcomes in this complex and heterogeneous disease.
2024-08-19 | Current Therapies and Future Horizons in Cardiac Amyloidosis Treatment.
Cardiac amyloidosis (CA) is a condition characterized by misfolding and extracellular deposition of proteins, leading to organ dysfunction. While numerous forms of CA exist, two subtypes dominate clinical prevalence: Transthyretin amyloid (ATTR) and immunoglobulin light chain amyloid. The current scientific landscape reflects the urgency to advance therapeutic interventions with over 100 ongoing clinical trials. Heart failure treatment is affected by CA phenotype with poor tolerance of otherwise frequently used medications. Treating comorbidities including atrial fibrillation and valvular disease remains a challenge in CA, driven by technical difficulties and uncertain outcomes. Tafamidis is the first ATTR-stabilizer approved with a rapidly growing rate of clinical use. In parallel, various new therapeutic classes are in late-stage clinical trials including silencers, antibodies and genetic therapy. Managing CA is a critical challenge for future heart failure care. This review delineates the current standard-of-care and scientific landscape of CA therapy.
2024-04-01 | 381 BiP knockdown decreases antibody production in malignant and non-malignant plasma cells
OBJECTIVES/GOALS: Numerous diseases, including AL amyloidosis, are due to expression of aberrant antibodies. Significant effort has gone into plasma cell toxic therapies with varying degrees of success, but no therapies preventing antibody synthesis have been developed. The goal of this study is to assess BiP targeting to prevent antibody secretion in plasma cells. METHODS/STUDY POPULATION: Using 4 multiple myeloma cell lines (KMS11, RPMI8226, ANBL-6, U266), we knocked down BiP expression with RnaseH dependent siRNA or subA toxin, a bacterial toxin that specifically cleaves BiP, and measured changes in unfolded protein and intracellular light chains by flow cytometry during drug induced ER stress created by the intracellular calcium depleting agent thapsigargin. BiP is the master regulator of the unfolded protein response (UPR), an ER stress pathway important for protein folding. BiP is also an ER resident protein folding chaperone important for proper antibody folding. We hypothesized that BiP downregulation will lead to decreased folded antibody in the cell, increased unfolded antibody and constitutive activation of the UPR. RESULTS/ANTICIPATED RESULTS: 1 to 4 hours after treatment with thapsigargin plus siRNA against BiP, levels of BiP are significantly decreased. The levels of intracellular light chains decrease, and the level of unfolded protein within the cells increases dramatically. Interestingly, in alignment with the UPR literature, 24 hours post treatment, these levels have normalized again in surviving cells. SubA treatment increased BiP expression by 4 hours, contrary to our hypothesis, and minimally increased unfolded proteins and minimally decreased intracellular light chains. We expect that further functional testing of antibody secretion by ELIspot assays will show decreased secretion of antibody with BiP siRNA treatment. Combination therapies with other UPR stressing agents may act synergistically to affect antibody production. DISCUSSION/SIGNIFICANCE: BiP knockdown reduces antibodies and boosts unfolded proteins. SubA toxin ineffectiveness likely stems from increased BiP due to feedback loops. Combining anti-BiP treatments with UPR stressing drugs like bortezomib may halt antibody synthesis and induce cell death. These findings support BiP as a viable drug target for antibody-related diseases.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
26 orphan drug designations for AL amyloidosis, including 2 approved therapies.
26 orphan drug designations for AL amyloidosis, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
zamubafusp alfa | proteins | FDA | 2026-06-01 | — | Attralus, Inc. |
revlucabtagene autoleucel | cell therapies | FDA | 2025-12-02 | — | Nexcella, Inc. |
Humanised IgG1 monoclonal antibody against misfolded immunoglobulin G, fused with pan-amyloid-reactive peptide p5R | antibodies | EMA | 2024-08-21 | — | Raremoon Consulting Esp S.L. |
Autologous CD3-positive T-cells expressing a chimeric antigen receptor against B cell maturation agent | cell therapies | EMA | 2024-02-19 | — | Raremoon Consulting Esp S.L. |
Bortezomib | small molecules | EMA | 2023-11-08 | — | Accord Healthcare S.L. |
Autologous T cells expressing anti-B cell maturation agent chimeric antigen receptor | cell therapies | FDA | 2023-09-19 | — | Nexcella, Inc. |
Iodine (I124) evuzamitide | small molecules | FDA | 2022-11-14 | — | Attralus, Inc. |
Iodine (124I) evuzamitide | proteins | EMA | 2022-11-10 | — | Raremoon Consulting Esp S.L. |
daratumumab and hyaluronidase-fihj [Darzalex Faspro] | antibodies | FDA | 2020-10-06 | 2021-01-15 | Janssen Research & Development, LLC |
Florbetaben (18F) | small molecules | EMA | 2020-04-22 | — | Lantheus Germany GmbH |
florbetaben F18 | small molecules | FDA | 2020-04-07 | — | Lantheus Biosciences Ltd. |
Chimeric fibril-reactive IgG1k monoclonal antibody 11-1F4 | antibodies | EMA | 2019-11-13 | — | Alexion Europe S.A.S. |
Daratumumab [Darzalex] | antibodies | EMA | 2018-05-25 | 2021-06-23 | Janssen-Cilag International NV |
daratumumab | antibodies | FDA | 2017-09-05 | — | Janssen Research & Development, LLC |
carboxy pyrrolidine hexanoyl pyrrolidine carboxylate | small molecules | FDA | 2015-02-10 | — | Glaxo Group Limited, England d/b/a GlaxoSmithKline |
recombinant monoclonal antibody to human serum amyloid P component | antibodies | FDA | 2015-02-10 | — | Glaxo Group Limited, England d/b/a GlaxoSmithKline |
N-(3,4-dihydroxyphenyl)-3,4-dihydroxybenzamide | small molecules | FDA | 2014-10-15 | — | ProtaMed, Inc. |
Miridesap [GSK2315698] | small molecules | EMA | 2014-07-29 | — | Glaxosmithkline Trading Services Limited |
Dezamizumab [GSK2398852] | antibodies | EMA | 2014-07-29 | — | Glaxosmithkline Trading Services Limited |
Revusiran | RNAs | EMA | 2014-04-29 | — | Alnylam UK Limited |
Humanised IgG1 kappa antibody against serum amyloid A and AL amyloid | antibodies | EMA | 2013-02-08 | — | Prothena Biosciences Limited |
Ixazomib citrate [Ninlaro] | small molecules | EMA | 2012-11-08 | — | Takeda Pharma A/S |
2,2'-{2-[1R)-1-({[(2,5-dichlorobenzoyl)amino]acetyl}amino)-3-methylbutyl]-5-oxo-1,3,2-dioxaborolane-4,4-diyl}diacetic acid (ixazomib citrate) | small molecules | FDA | 2012-03-09 | — | Millennium Pharmaceuticals, Inc. |
monoclonal antibody 11-1F4 | antibodies | FDA | 2009-12-11 | — | Caelum Biosciences, Inc. |
Tafamidis meglumine [Vyndaqel] | small molecules | EMA | 2006-08-28 | — | Pfizer Europe MA EEIG |
Iodine (123I) serum amyloid P component [Amysap] | proteins | EMA | 2003-02-14 | — | [INACTIVE] Laboratoire Francais Du Fractionnement Et Des Biotechnologies |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.