scholarly journals CD38 and Anti-CD38 Monoclonal Antibodies in AL Amyloidosis: Targeting Plasma Cells and beyond

2020 ◽  
Vol 21 (11) ◽  
pp. 4129 ◽  
Author(s):  
Dario Roccatello ◽  
Roberta Fenoglio ◽  
Savino Sciascia ◽  
Carla Naretto ◽  
Daniela Rossi ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Plasma Cells ◽  
Nk Cell ◽  
Therapeutic Potential ◽  
Systemic Disease ◽  
Neoplastic Transformation ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Immunoglobulin Light Chain Amyloidosis

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare systemic disease characterized by monoclonal light chains (LCs) depositing in tissue as insoluble fibrils, causing irreversible tissue damage. The mechanisms involved in aggregation and deposition of LCs are not fully understood, but CD138/38 plasma cells (PCs) are undoubtedly involved in monoclonal LC production.CD38 is a pleiotropic molecule detectable on the surface of PCs and maintained during the neoplastic transformation in multiple myeloma (MM). CD38 is expressed on T, B and NK cell populations as well, though at a lower cell surface density. CD38 is an ideal target in the management of PC dyscrasia, including AL amyloidosis, and indeed anti-CD38 monoclonal antibodies (MoAbs) have promising therapeutic potential. Anti-CD38 MoAbs act both as PC-depleting agents and as modulators of the balance of the immune cells. These aspects, together with their interaction with Fc receptors (FcRs) and neonatal FcRs, are specifically addressed in this paper. Moreover, the initiallyavailable experiences with the anti-CD38 MoAb DARA in AL amyloidosis are reviewed.

scholarly journals Immunoglobulin light chain amyloidosis

2021 ◽  
Author(s):  
Hermine Agis ◽  
Maria T. Krauth
Keyword(s):  
Light Chain ◽  
Systemic Disease ◽  
Correct Diagnosis ◽  
Organ Damage ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Multiprofessional Team ◽  
Assessment And Treatment ◽  
Life Threatening ◽  
Immunoglobulin Light Chain Amyloidosis

SummaryImmunoglobulin light chain (AL) amyloidosis is a rare and underdiagnosed life-threatening systemic disease, primarily caused by insoluble depositions of misfolded monoclonal light chains. The monoclonal light chain paraprotein originates from a small clonal B‑cell or a clonal plasma cell population. If left undetected the paraprotein can induce a number of complications based on organ damage. The most dangerous and life-threatening organ dysfunction emerges from cardiac involvement. Thus, patients overall survival depends on early detection. Establishing the correct diagnosis and clear characterization of the amyloid-forming protein, staging, risk assessment and treatment are crucial and depend on a highly experienced interdisciplinary, multiprofessional team.

scholarly journals Systemic Light Chain Amyloidosis (Congo Red Inconclusive) with Underlyng Clonal Expansion Not Meeting the Criteria of Light Chain Monoclonal Gammopathy of Renal Significance or Light Chain Myeloma:A Case Report

2020 ◽  
Vol 07 (04) ◽  
pp. 15-19
Author(s):  
Sanjay Kumar ◽  
Keyword(s):  
Light Chain ◽  
Congo Red ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Clonal Expansion ◽  
Chronic Diarrhoea ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Light Chain Amyloidosis ◽  
Immunoglobulin Light Chain Amyloidosis

Fifty-eight-year-old male admitted for evaluation of nephrotic syndrome and chronic diarrhoea was detected to have Immunoglobulin light chain amyloidosis (AL Amyloidosis) which was congo red inconclusive from renal biopsy. Bone marrow biopsy showed monoclonal plasma cells of 40% and light chain assay showed predominance of immunoglobulin lambda light chain. The diagnosis was neither fitting into the current diagnostic criteria for light chain Monoclonal Gammopathy of Renal Significance (MGRS) nor light chain myeloma. Literature is scarce regarding patients with AL amyloidosis having underlying clonal expansion not meeting the criteria of light chain myeloma or light chain MGRS.

scholarly journals Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis

Hemato ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 645-659
Author(s):  
Gareth J. Morgan ◽  
Joel N. Buxbaum ◽  
Jeffery W. Kelly
Keyword(s):  
Light Chain ◽  
Plasma Cells ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Organ Function ◽  
Conserved Residues ◽  
Light Chain Amyloidosis ◽  
Emerging Therapies ◽  
Chain Conformations

Non-native immunoglobulin light chain conformations, including aggregates, appear to cause light chain amyloidosis pathology. Despite significant progress in pharmacological eradication of the neoplastic plasma cells that secrete these light chains, in many patients impaired organ function remains. The impairment is apparently due to a subset of resistant plasma cells that continue to secrete misfolding-prone light chains. These light chains are susceptible to the proteolytic cleavage that may enable light chain aggregation. We propose that small molecules that preferentially bind to the natively folded state of full-length light chains could act as pharmacological kinetic stabilizers, protecting light chains against unfolding, proteolysis and aggregation. Although the sequence of the pathological light chain is unique to each patient, fortunately light chains have highly conserved residues that form binding sites for small molecule kinetic stabilizers. We envision that such stabilizers could complement existing and emerging therapies to benefit light chain amyloidosis patients.

scholarly journals Increased Serum Free Light Chains Precede the Presentation of Immunoglobulin Light Chain Amyloidosis

2014 ◽  
Vol 32 (25) ◽  
pp. 2699-2704 ◽  
Author(s):  
Brendan M. Weiss ◽  
Joseph Hebreo ◽  
Daniel V. Cordaro ◽  
Mark J. Roschewski ◽  
Thomas P. Baker ◽  
...  
Keyword(s):  
Light Chain ◽  
Early Death ◽  
Immunoglobulin M ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Serum Free ◽  
Light Chain Amyloidosis ◽  
Serum Free Light Chain ◽  
Immunoglobulin Light Chain Amyloidosis

PurposePatients with immunoglobulin light chain amyloidosis (AL amyloidosis) generally present with advanced organ dysfunction and have a high risk of early death. We sought to characterize monoclonal immunoglobulin (M-Ig) light chains before clinical presentation of AL amyloidosis.Patients and MethodsWe obtained prediagnostic sera from 20 cases with AL amyloidosis and 20 healthy controls matched for age, sex, race, and age of serum sample from the Department of Defense Serum Repository. Serum protein electrophoresis with immunofixation and serum free light chain (FLC) analysis were performed on all samples.ResultsAn M-Ig was detected in 100% of cases and 0% of controls (P < .001). The M-Ig was present in 100%, 80%, and 42% of cases at less than 4 years, 4 to 11 years, and more than 11 years before diagnosis, respectively. The median FLC differential (FLC-diff) was higher in cases compared with controls at all time periods, less than 4 years (174.8 v 0.3 mg/L; P < .001), 4 to 11 years (65.1 v 2.2 mg/L; P < .001), and more than 11 years (4.5 v 0.4 mg/L; P = .03) before diagnosis. The FLC-diff was greater than 23 mg/L in 85% of cases and 0% of controls (P < .001). The FLC-diff level increased more than 10% per year in 84% of cases compared with 16% of controls (P < .001).ConclusionIncrease of FLCs, including within the accepted normal range, precedes the development of AL amyloidosis for many years.

scholarly journals Splenic plasma cells can serve as a source of amyloidogenic light chains

Blood ◽  
2009 ◽  
Vol 113 (7) ◽  
pp. 1501-1503 ◽  
Author(s):  
Alan Solomon ◽  
Sallie D. Macy ◽  
Craig Wooliver ◽  
Deborah T. Weiss ◽  
Per Westermark
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Monoclonal Antibodies ◽  
Light Chain ◽  
Plasma Cells ◽  
The Body ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Hematopoietic Organ ◽  
Significant Evidence

Abstract Bone marrow-derived clonal plasma cells, as found in systemic amyloidogenic light chain–associated (AL) amyloidosis, are presumed to be the source of light chains that deposit as fibrils in tissues throughout the body. Paradoxically, people with this disorder, in contrast to multiple myeloma, often have a low percentage of such cells, and it is unknown whether this relatively sparse number can synthesize enough amyloidogenic precursor to form the extensive pathology that occurs. To investigate whether another hematopoietic organ, the spleen, also contains monoclonal light chain–producing plasma cells, we have immunostained such tissue from 26 AL patients with the use of antiplasma cell, antifree κ and λ, and anti-VL subgroup-specific monoclonal antibodies (mAbs). In 12 cases, there was statistically significant evidence of a monoclonal population bearing the same κ or λ isotype as that within the bone marrow and identical to the amyloid. Our studies have shown that the spleen may be another source of amyloidogenic light chains.

scholarly journals A Unique Case of Combined Nodular and Tracheobronchial Amyloidosis

2021 ◽  
Vol 2021 (2) ◽  
Author(s):  
Feihong Ding ◽  
Yun Li ◽  
Shailesh Balasubramanian ◽  
Subha Ghosh ◽  
Jason N Valent ◽  
...  
Keyword(s):  
Light Chain ◽  
Systemic Disease ◽  
Amyloid Deposition ◽  
Misfolded Proteins ◽  
Immunoglobulin Light Chain ◽  
Anatomic Site ◽  
Unique Case ◽  
Pulmonary Amyloidosis ◽  
Immunoglobulin Light Chain Amyloidosis ◽  
Tracheobronchial Amyloidosis

ABSTRACT Amyloidosis is a heterogeneous group of diseases characterized by the extracellular deposition of misfolded proteins that can affect either systemically or locally confined to one system. Pulmonary amyloidosis is rare and can be classified into three forms according to the anatomic site of involvement: nodular pulmonary amyloidosis, tracheobronchial amyloidosis and diffuse alveolar-septal amyloidosis. The former two usually represent localized amyloid disease and the latter represents systemic disease. Typically lung parenchymal and tracheobronchial amyloidosis do not present together in localized forms of pulmonary amyloidosis. Here we report a unique case of localized pulmonary immunoglobulin light-chain amyloidosis, manifested as both parenchymal nodules and tracheobronchial amyloid deposition.

scholarly journals Beyond the plasma cell: emerging therapies for immunoglobulin light chain amyloidosis

Blood ◽  
2016 ◽  
Vol 127 (19) ◽  
pp. 2275-2280 ◽  
Author(s):  
Brendan M. Weiss ◽  
Sandy W. Wong ◽  
Raymond L. Comenzo
Keyword(s):  
Light Chain ◽  
Plasma Cells ◽  
Organ Damage ◽  
Immunoglobulin Light Chain ◽  
Organ Function ◽  
Fatal Disease ◽  
Mortality And Morbidity ◽  
Amyloid Deposits ◽  
Emerging Therapies ◽  
Immunoglobulin Light Chain Amyloidosis

Abstract Systemic immunoglobulin light chain (LC) amyloidosis (AL) is a potentially fatal disease caused by immunoglobulin LC produced by clonal plasma cells. These LC form both toxic oligomers and amyloid deposits disrupting vital organ function. Despite reduction of LC by chemotherapy, the restoration of organ function is highly variable and often incomplete. Organ damage remains the major source of mortality and morbidity in AL. This review focuses on the challenges posed by emerging therapies that may limit the toxicity of LC and improve organ function by accelerating the resorption of amyloid deposits.

scholarly journals Silver Nanoparticle-Based Assay for the Detection of Immunoglobulin Free Light Chains

Materials ◽  
2019 ◽  
Vol 12 (18) ◽  
pp. 2981 ◽  
Author(s):  
Anna Lizoń ◽  
Magdalena Wytrwal-Sarna ◽  
Marta Gajewska ◽  
Ryszard Drożdż
Keyword(s):  
Light Scattering ◽  
Silver Nanoparticle ◽  
Plasma Cells ◽  
Wide Spectrum ◽  
Metal Nanoparticle ◽  
Light Chains ◽  
Hydrodynamic Diameter ◽  
Al Amyloidosis ◽  
Free Light Chains ◽  
Optimal Test

There is a wide spectrum of malignant diseases that are connected with the clonal proliferation of plasma cells, which cause the production of complete immunoglobulins or their fragments (heavy or light immunoglobulin chains). These proteins may accumulate in tissues, leading to end organ damage. The quantitative determination of immunoglobulin free light chains (FLCs) is considered to be the gold standard in the detection and treatment of multiple myeloma (MM) and amyloid light-chain (AL) amyloidosis. In this study, a silver nanoparticle-based diagnostic tool for the quantitation of FLCs is presented. The optimal test conditions were achieved when a metal nanoparticle (MNP) was covered with 10 particles of an antibody and conjugated by 5–50 protein antigen particles (FLCs). The formation of the second antigen protein corona was accompanied by noticeable changes in the surface plasmon resonance spectra of the silver nanoparticles (AgNPs), which coincided with an increase of the hydrodynamic diameter and increase in the zeta potential, as demonstrated by dynamic light scattering (DLS). A decrease of repulsion forces and the formation of antigen–antibody bridges resulted in the agglutination of AgNPs, as demonstrated by transmission electron microscopy and the direct formation of AgNP aggregates. Antigen-conjugated AgNPs clusters were also found by direct observation using green laser light scattering. The parameters of the specific immunochemical aggregation process consistent with the sizes of AgNPs and the protein particles that coat them were confirmed by four physical methods, yielding complementary data concerning a clinically useful AgNPs aggregation test.

scholarly journals Hereditary systemic immunoglobulin light-chain amyloidosis

Blood ◽  
2015 ◽  
Vol 125 (21) ◽  
pp. 3281-3286 ◽  
Author(s):  
Merrill D. Benson ◽  
Juris J. Liepnieks ◽  
Barbara Kluve-Beckerman
Keyword(s):  
Light Chain ◽  
Plasma Cell Dyscrasia ◽  
Al Amyloidosis ◽  
Constant Region ◽  
Immunoglobulin Light Chain ◽  
Region Gene ◽  
Dna Analyses ◽  
Key Points ◽  
Constant Region Gene ◽  
Immunoglobulin Light Chain Amyloidosis

Key Points Protein and DNA analyses reveal that mutation in the immunoglobulin κ light-chain constant region gene may cause hereditary amyloidosis. Sequencing of immunoglobulin light-chain constant region genes is indicated for patients with AL amyloidosis and no evidence of a plasma cell dyscrasia.

scholarly journals Immunoglobulin Light-Chain Amyloidosis: From Basics to New Developments in Diagnosis, Prognosis and Therapy

2016 ◽  
Vol 135 (3) ◽  
pp. 172-190 ◽  
Author(s):  
Eli Muchtar ◽  
Francis K. Buadi ◽  
Angela Dispenzieri ◽  
Morie A. Gertz
Keyword(s):  
Light Chain ◽  
Plasma Cells ◽  
Treatment Options ◽  
Organ Damage ◽  
Major Effect ◽  
Response To Treatment ◽  
Al Amyloidosis ◽  
Prognostic Effect ◽  
Amyloid Light Chain ◽  
Immunoglobulin Light Chain Amyloidosis

Immunoglobulin amyloid light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, where the culprit amyloidogenic protein is immunoglobulin light chains produced by marrow clonal plasma cells. AL amyloidosis is an infrequent disease, and since presentation is variable and often nonspecific, diagnosis is often delayed. This results in cumulative organ damage and has a negative prognostic effect. AL amyloidosis can also be challenging on the diagnostic level, especially when demonstration of Congo red-positive tissue is not readily obtained. Since as many as 31 known amyloidogenic proteins have been identified to date, determination of the amyloid type is required. While several typing methods are available, mass spectrometry has become the gold standard for amyloid typing. Upon confirming the diagnosis of amyloidosis, a pursuit for organ involvement is essential, with a focus on heart involvement, even in the absence of suggestive symptoms for involvement, as this has both prognostic and treatment implications. Details regarding initial treatment options, including stem cell transplantation, are provided in this review. AL amyloidosis management requires a multidisciplinary approach with careful patient monitoring, as organ impairment has a major effect on morbidity and treatment tolerability until a response to treatment is achieved and recovery emerges.

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