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 Long-term Follow-up of Plasma Cells in Bone Marrow and Serum Free Light Chains in Primary Systemic AL Amyloidosis

2008 ◽  
Vol 47 (20) ◽  
pp. 1783-1790 ◽  
Author(s):  
Takuhiro Yoshida ◽  
Masayuki Matsuda ◽  
Nagaaki Katoh ◽  
Ko-ichi Tazawa ◽  
Yasuhiro Shimojima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Free Light Chains ◽  
Serum Free ◽  
Long Term Follow Up ◽  
Serum Free Light Chains

Measurement of Serum Free Light Chains in AL Amyloidosis

2004 ◽  
pp. 154-156
Author(s):  
H.D. Carr-Smith ◽  
R. Abraham ◽  
G.P. Mead ◽  
H. Goodman ◽  
P. Hawkins ◽  
...  
Keyword(s):  
Light Chains ◽  
Al Amyloidosis ◽  
Free Light Chains ◽  
Serum Free ◽  
Serum Free Light Chains

scholarly journals Quantitative Immunoprecipitation Free Light Chain Mass Spectrometry (QIP-FLC-MS) Simplifies Monoclonal Protein Assessment and Provides Added Clinical Value in Systemic AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4375-4375 ◽  
Author(s):  
Faye Amelia Sharpley ◽  
Hannah Victoria Giles ◽  
Richa Manwani ◽  
Shameem Mahmood ◽  
Sajitha Sachchithanantham ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Light Chain ◽  
Residual Disease ◽  
Renal Involvement ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Free Light Chains ◽  
Accurate Identification ◽  
Monoclonal Protein ◽  
Serum And Urine

Introduction Early diagnosis, effective therapy and precise monitoring are central for improving clinical outcomes in systemic light chain (AL) amyloidosis. Diagnosis and disease response assessment is primarily based on the presence of monoclonal immunoglobulins and free light chains (FLC). The ideal goal of therapy associated with best outcomes is a complete responses (CR), defined by the absence of serological clonal markers. In both instances, detection of the monoclonal component (M-component) is based on serum FLC assessment together with traditional serum and urine electrophoretic approaches, which present inherent limitations and lack sensitivity particularly in AL where the levels are typically low. Novel mass spectrometry methods provide sensitive, accurate identification of the M-component and may prove instrumental in the timely management of patients with low-level amyloidogenic light chain production. Here we assess the performance of quantitative immunoprecipitation FLC mass spectrometry (QIP-FLC-MS) at diagnosis and during monitoring of AL amyloidosis patients treated with bortezomib-based regimens. Methods We included 46 serial patients with systemic AL amyloidosis diagnosed and treated at the UK National Amyloidosis Centre (UK-NAC). All patients had detailed baseline assessments of organ function and serum FLC measurements. Baseline, +6- and +12-month serum samples were retrospectively analysed by QIP-FLC-MS. Briefly, magnetic microparticles were covalently coated with modified polyclonal sheep antibodies monospecific for free kappa light chains (anti-free κ) and free lambda light chains (anti-free λ). The microparticles were incubated with patient sera, washed and treated with acetic acid (5% v/v) containing TCEP (20 mM) in order to elute FLC in monomeric form. Mass spectra were acquired on a MALDI-TOF-MS system (Bruker, GmbH). Results were compared to serum FLC measurements (Freelite®, The Binding Site Group Ltd), as well as electrophoretic assessment of serum and urine proteins (SPE, sIFE, UPE and uIFE). Results Cardiac (37(80%) patients) and renal (31(67%) patients) involvement were most common; 25(54%) patients presented with both. Other organs involved included liver (n=12), soft tissue (n=4), gastrointestinal tract (n=3) and peripheral nervous system (n=2). Baseline Freelite, SPE, sIFE and uIFE measurements identified a monoclonal protein in 42(91%), 22(48%), 34(74%) and 21(46%) patients, respectively. A panel consisting of Freelite + sIFE identified the M-component in 100% of the samples. QIP-FLC-MS alone also identified an M-component in 100% of the samples and was 100% concordant with Freelite for typing the monoclonal FLC (8 kappa, 34 lambda). In 4 patients, QIP-FLC-MS identified an additional M-protein that was not detected by the other techniques. In addition, 4/8(50%) kappa and 4/38(11%) lambda patients showed a glycosylation pattern of monoclonal FLCs at baseline by mass spectrometry. Interestingly, the frequency of renal involvement was significantly lower for patients with non-glycosylated forms (25% vs 76%, p=0.01), while no similar relationship was found for any other organs. During the 1-year follow-up period, 17 patients achieved a CR; QIP-FLC-MS identified serum residual disease in 13(76%) of these patients. Conclusion In our series, QIP-FLC-MS was concordant with current serum methods for identifying the amyloidogenic light chain type and provided, against all other individual tests, improved sensitivity for the detection of the monoclonal protein at diagnosis and during monitoring. The ability to measure the unique molecular mass of each monoclonal protein offers clone-specific tracking over time. Glycosylation of free light chains is over-represented in AL patients which may allow earlier diagnosis and better risk-assessment of organ involvement. Persistence of QIP-FLC-MS positive M component in patients otherwise in CR may allow targeted therapy. Overall, QIP-FLC-MS demonstrates potential to be exploited as a single serum test for precise serial assessment of monoclonal proteins in patients with AL amyloidosis. Disclosures Wechalekar: GSK: Honoraria; Janssen-Cilag: Honoraria; Amgen: Research Funding; Takeda: Honoraria; Celgene: Honoraria.

Biclonal Multiple Myeloma with Monoclonal Free IgG3 Heavy Chain and kappa Free Light Chains.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4768-4768
Author(s):  
Alex G. Richter ◽  
Stephen Harding ◽  
Steve Rimmer ◽  
Guy Pratt ◽  
Aarnoud Huissoon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Western Blot ◽  
Heavy Chain ◽  
Light Chain ◽  
Lymphoproliferative Disorder ◽  
Plasma Cells ◽  
Light Chains ◽  
Cell Transplant ◽  
Free Light Chains ◽  
Night Sweats

Abstract Background: Heavy chain disease (HCD) is a rare lymphoproliferative disorder characterized by a monoclonal heavy chain (HC) unattached to a light chain (LC). IgGHCD or γHCD typically presents as a lymphoproliferative disorder with lymphadenopathy and hepatosplenomegaly. Myeloma has been described associated with γHCD but only with a second intact Ig paraprotein. This report describes a unique presentation of multiple myeloma with monoclonal free γ3HC and kappa free light chains. Case: A 34 year old gentleman presented with mild persistent neutropenia following two episodes of pneumonia, 18 months previously. He admitted to persistent night sweats but no other significant history. Baseline investigations revealed a mild anaemia, neutropenia and a large IgG paraprotein with no associated light chain. Bone marrow aspirate and trephine confirmed myeloma. The patient was treated with cyclophosphamide, thalidomide and dexamethasone and has had a very good partial remission. He is awaiting a sibling allogeneic peripheral blood stem cell transplant. Investigations and results: Serum Electrophoresis confirmed a large IgG paraprotein (23g/l) with no associated light chain in the serum and identified as γ3 subclass by radial immunodiffusion. Western blot showed the γ3HC was truncated with a large deletion. Markedly elevated free kappa (κ) LC (503.58 mg/l [3.30–19.4]) were found in the serum with gross skewing of the kappa/lambda ratio. Urine electrophoresis revealed separate γHC and κ LC paraproteins. Western blot of the fractionated urine protein demonstrated different sized κLC aggregates. Flow cytometry of the marrow aspirate revealed an unusual staining pattern; CD5,19,38,45+ve and CD20,22,23,34,56,138 –ve plasma cells. Cytoplasmic staining revealed 2 distinct populations of plasma cells, the first producing γ3HC and the second only free κLC. Cytogenetics and FISH analysis for 14q, p53 and c-myc abnormalities were normal. Discussion: This is the first description of a Biclonal Myeloma with separate plasma cell populations producing γ3HC and κLC paraproteins. The biclonality confirms the free HC occurs as a result of abnormal synthesis not cleavage. The clinical and immunological findings are clearly different to typical findings in both γ3HCD and Myeloma. HCD has an appalling prognosis and this case is likely to have been ‘smouldering’ for 18 months, evidenced by the 2 pneumonias and persistent night sweats. There is no lymphadenopathy or organomegaly associated with γ3HCD. The immunophenotype of the malignant plasma cells is unique. Other atypical features include frank proteinuria, with a HC in the urine, but normal renal function and no radiological or biochemical evidence of bone involvement. We propose that this unique biclonal myeloma has distinct immunological and clinical features.

scholarly journals Clonal plasma cells in AL amyloidosis are dependent on pro survival BCL-2 family proteins and sensitive to BH3 mimetics

2019 ◽  
Author(s):  
Cameron Fraser ◽  
Adam Presser ◽  
Vaishali Sanchorawala ◽  
Shayna Sarosiek ◽  
Kristopher Sarosiek
Keyword(s):  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Single Agent ◽  
Current Treatment ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Current Standard ◽  
Bh3 Mimetics

Immunoglobulin light chain (AL) amyloidosis is a protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains misfold and accumulate as amyloid fibrils in healthy tissues causing devastating multi-organ dysfunction that is rapidly fatal. Current treatment regimens, which include proteasome inhibitors, alkylating agents, and immunomodulatory agents, were developed for the treatment of the more common plasma cell disease, multiple myeloma, and have limited efficacy in AL amyloidosis as demonstrated by the median survival of 2-3 years. The recent development of novel small-molecule inhibitors of the major pro-survival proteins from the apoptosis-regulating BCL-2 family has created an opportunity to therapeutically target abnormal cell populations, yet identifying the extent of these dependencies and how to target them clinically has thus far been challenging. Using bone marrow-derived plasma cells from 45 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins. Specifically, we find that clonal plasma cells in a majority of patients are highly dependent on the pro-survival protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor as a single agent. In addition, BCL-2 inhibition sensitizes clonal plasma cells to several current standard of care therapies. Our results suggest that BH3 mimetics, when deployed rationally, may be highly effective therapies for AL amyloidosis.

scholarly journals AL Amyloidosis — Pathogenesis and Prognosis Are Determined By the Amyloidogenic Potential of the Light Chain and the Molecular Characteristics of Malignant Plasma Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 187-187
Author(s):  
Anja Seckinger ◽  
Ute Hegenbart ◽  
Susanne Beck ◽  
Martina Emde ◽  
Tilmann Bochtler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Plasma Cell ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Light Chains ◽  
Molecular Characteristics ◽  
Al Amyloidosis ◽  
Malignant Plasma Cell

Abstract INTRODUCTION. Systemic light chain amyloidosis (AL) is caused by accumulation of plasma cells producing misfolded monoclonal light chains depositing as amyloid fibrils in different organs, most frequently heart and kidney. AIM of our study is first assessing the molecular characteristics of malignant plasma cells from AL-patients in relation to those from MGUS, asymptomatic, and symptomatic myeloma: Are these plasma cells different, does this difference explain amyloidogenicity? Does AL correspond to a certain developmental stage during evolution of symptomatic myeloma? Secondly, to what extent is prognosis determined by amyloid-deposition (organotropism, amount, amyloidogenicity) vs. number and molecular characteristics of malignant plasma cells? PATIENTS & METHODS . Consecutive patients (n=3023) with AL (n=582), MGUS (n=306), asymptomatic (n=444, AMM), or previously untreated, therapy-requiring multiple myeloma (n=1691, MM) were included. CD138-purified plasma cell samples were subjected to iFISH (n=582/306/444/1691), 1297 to gene expression profiling using Affymetrix U133 2.0 plus arrays (n=196/64/272/765), 712 to RNA- (n=124/52/38/489), and 258 to whole exome sequencing (n=115/53/39/51). Samples of normal bone marrow plasma cells, memory B-cells, and polyclonal plasmablasts were used as comparators. The CoMMpass-cohort (n=647) was used as comparator for the mutational spectrum of myeloma. RESULTS . Prognosis. By AL-factors. Expectedly, organ involvement, i.e. heart only vs. kidney only vs. heart+kidney vs. other (overall survival (OS), P=.001), the amount of free light chains (dFLC ≥18 mg/dL, HR=2.56, P=.01), and the cardiac European Mayo IIIB score (I/II/IIIA/IIIB, median OS 110/55/16/3 months, HR=1/1.94/3.73/7.90, P<.001) strongly determine prognosis (Fig. 1A). By malignant plasma cell factors. High proliferation rate (HR=3.58, P=.001) and expression-based risk factors for MM (GEP70 high, HR=2.38, P=.005; Rs-score high HR=4.63, P<.001) identify patients with very adverse prognosis (Fig. 1A). Tumor load, e.g. plasma cell infiltration >10%/>30% (HR=1.31/1.81, P=.01, P=.002) and M-protein ≥ 30g/l (HR=3.01, P=.005), are likewise prognostic (Fig. 1A). In multivariate analysis, all tested AL-specific (European Mayo IIIB score) and malignant plasma cell factors (proliferation or GEP70 and plasma cell infiltration) are independent. Molecular characteristics.iFISH. As MM (96.2%) and AMM (92.8%) AL-patients (93.1%) carry at least one recurrent myeloma typical aberration. The mean number of progression-associated aberrations in AL (n=0.98) fits between MGUS (n=0.85) and AMM (n=1.45) with significant difference compared to AMM (P<.001) unlike to MGUS. Main differences in frequency are found for t(11;14) and hyperdiploidy with a comparable pattern of non-etiologic aberrations. Gene expression (GEP and RNA-seq). Aberrant plasma cells in AL amyloidosis show the least difference with AMM, followed by MGUS and MM. In principal component analysis, AL overlaps with AMM and MGUS, independent of presence or absence of heart involvement (Fig. 1B). Pairwise assessment of similarity using a multivariate generalization of the squared Pearson correlation coefficient shows closest similarity to AMM and MM followed by MGUS, with comparable differences to normal plasma cells, polyclonal plasmablasts, and memory B-cells. Significantly more AL-patients present with higher proliferation rate vs MGUS (P<.001) and AMM (P<.02). AL and MM differ significantly regarding distinct molecular entities as determined by GEP (e.g. TC-classification; Fig. 1C). Mutation spectrum in AL amyloidosis vs. MM. From the 20 most frequently synonymously mutated non-Ig transcripts (CoMMpass-cohort), 16 could likewise be detected in AL amyloidosis, i.e. KRAS, NRAS, IGLL5, DIS3, FAM46C, MUC16, BRAF, TRAF3, PCLO, RYR2, FATA4, CSMD3, TP53, DNAH5, RYR2A, and FLG. CCND1 mutations were significantly more frequent in AL and AMM compared to MM (P=.02). DISCUSSION & CONCLUSION. Pathogenesis and prognosis of AL amyloidosis are explained both by AL-specific and malignant plasma cell characteristics. Aberrant plasma cells in AL amyloidosis show the same aberration- and expression pattern and a "molecular age" between MGUS and AMM, most closely resembling the latter. AL amyloidosis is thus mostly a rather early plasma cell dyscrasia with an unstable and toxic immunoglobulin light chain. Disclosures Seckinger: Celgene: Research Funding; EngMab: Research Funding; Sanofi: Research Funding. Hose:Celgene: Honoraria, Research Funding; Sanofi: Research Funding; EngMab: Research Funding.

scholarly journals Kidney Damage in the Manifestation of Lymphoproliferative Diseases

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5313-5313 ◽  
Author(s):  
Dzhumabaeva Tolgonbaevna Boldukyz ◽  
Birjukova Semenovna Ludmila ◽  
Julhakyan Hunan ◽  
Maryna Saliya ◽  
Roshchina Sergeevna Ludmila
Keyword(s):  
Renal Damage ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Lymphoproliferative Diseases ◽  
Free Light Chains ◽  
Large B Cell Lymphoma ◽  
Lymphoid Infiltration ◽  
Lymphoid Proliferation

Abstract Objectives: Kidney lesions at lymphoproliferative diseases mainly described with disease progression or relapse. Renal involvement in the manifestation of lymphoproliferative diseases were observed rarely. Pathogenesis of renal damage is obscure. Aim: To determine especially renal damage in the manifestation of lymphoproliferative diseases. Subjects and methods. The study included 19 patients (13 males, and 6 females, age 63.3±8.8 years) with lymphoproliferative diseases accompanied by renal failure: chronic lymphocytic leukemia (n=12), marginal zone lymphoma (n=4), follicular lymphoma (n=1), Waldenstrom's macroglobulinemia (n=1), diffuse large B-cell lymphoma (n=1). Nephrotic syndrome was observed in 3 patients and renal failure in 18 ones. The average creatinine level was 330.9±152.3 μmol/l, glomerular filtration rate was 25.7±12.9 ml/min. The presence of monoclonal IgMk secretion (n=6), Bence Jones protein kappa (n=9), increased level of free light chains (n=4), cryoglobulin (n=4). The renal biopsy was studied by histological, immunohistochemical, immunofluorescence, and electron microscopy. Results:Glomerulonephritises were revealed in 10 cases (52.6%): membranoproliferative glomerulonephritis (n=2), membranous (n=2), mesangiocapillary (n=3), fibrillary (n=1), immunotactoid glomerulonephritis (n=1), minimal-change disease (n=1). Neoplastic lymphoid infiltration of renal parenchyma was detected in 10 (52.6%) cases. The massive diffuse small cell lymphoid proliferation was determined in 1 case, focal infiltration in 9 ones. Neoplastic lymphoid infiltration was associated with glomerulonephritis in 3 cases and with carcinoma of the kidney in 4 cases. Large focal lymphoid proliferation was found in 1 case in a patient with diffuse large B-cell lymphoma. AL - amyloidosis was identified in 2 cases and the thrombotic microangiopathies in 2 ones. Conclusion. Glomerular disease, lymphoid tumor infiltration, sometimes AL - amyloidosis, thrombotic microangiopathy were detected in the manifestation of lymphatic tumor. In all cases examined, there was a secretion of monoclonal immunoglobulin, protein Bence Jones, free light chains and cryoglobulin, pathogenetic value in the development of glomerulopathy should be clarified. Disclosures No relevant conflicts of interest to declare.

Clinical Characteristics and Outcome of Primary AL Amyloidosis in Greece.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4729-4729
Author(s):  
Michalis Michail ◽  
Efstathios Kastritis ◽  
Sossana Delimpassi ◽  
Marie Christine Kyrtsonis ◽  
Evridiki Michali ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Autonomic Neuropathy ◽  
Congo Red ◽  
Plasma Cells ◽  
Primary Treatment ◽  
Response To Treatment ◽  
Light Chains ◽  
High Dose ◽  
Al Amyloidosis ◽  
Heart Involvement

Abstract Introduction: Primary systemic amyloidosis (AL) is a clonal plasma cells disorder characterized by deposition of amyloid fibrils derived from abnormal light chains, leading to multiorgan involvement and failure. There is no information regarding the clinical, laboratory, treatment characteristics and outcome of such patients in Greece. We performed a retrospective analysis in order to clarify these issues. Patients and Methods: Diagnosis of primary AL amyloidosis was based on positive Congo red staining, immunohistochemistry and the presence of typical clinical and laboratory features. Definition of organ involvement and treatment response was based on established criteria (Gertz et al Am J Hematol 2005). Results: between 1995 and 2007, we identified 109 patients with previously untreated systemic AL amyloidosis. Median age was 66.3 years; 51% were males and lambda-light chain was involved in 74% of patients. Bone marrow biopsy stained positive for Congo-red in 56.5%, immunohistochemical staining was performed in 80 cases: 63 (78.75%) stained positive for λ and 17 for κ light chains. A monoclonal protein by immunofixation was found in the serum and/or urine of 97 (87%) patients. More than 10% bone marrow plasma cells were found in 65%. B2microglobulin was elevated in 36% of patients (median value 2.8 mg/l). The most frequent symptoms at presentation were fatigue and weakness (81%). Heart was involved in 66 (59%), kidney in 79 (71%), liver in 21(19%), GI tract in 17 (16%) and soft tissue in 35 (32%) patients respectively. Symptoms of peripheral and/or autonomic neuropathy were present in 38 (35%) patients. More than two organs were involved in 50 patients (45%). Primary treatment with high-dose dexamethasone based regimens (VAD or pulse Dexamethasone) was used in 45% while 37% of patients were treated with melphalan and prednisone. Six patients (5%) were treated upfront with high dose melphalan and ASCT while another 6 patients were transplanted at a later stage of their disease. Hematologic response was achieved in 50 (46%) including 16 (14.5%) patients who achieved a CR. Organ responses were seen in 32 (29%) patients: 4 had cardiac, 21 renal and 7 liver response respectively while 11 patients had subjective improvement of peripheral or autonomic neuropathy. Median survival from initiation of treatment was 61 months and the 5 year-survival was 44%. Patients with heart involvement or with more than 2 affected organs had a worse prognosis. Survival was significantly longer for patients who responded to primary treatment than for those who did not (p=0.018). Conclusions: Greek patients with AL amyloidosis share the same characteristics with that of patients from other reported studies. Hematologic responses were noted in one-half and organ responses in one-third of patients. Prognosis depended primarily on the presence of heart involvement and on the lack of response to treatment.

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 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.

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