Immunodiagnostic Capabilities of Anti–Free Immunoglobulin Light Chain Monoclonal Antibodies

Davern, Sandra; Tang, Lian; Williams, T; Macy, Sallie; Wall, Jonathan S.; Weiss, Deborah; Solomon, Alan

doi:10.1309/ajcpns6k1cyjpdba

Cited by 28 publications

(26 citation statements)

References 33 publications

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“…All 18 patients entered on study (Table 1) 14 were HAMA-negative and had AL amyloidosis based on accepted clinical and laboratory criteria, 15 as well as (with 1 exception) the results of chemical analysis 16 of amyloid extracted from tissue or fat biopsy specimens. All subjects provided written informed consent in accordance with the Declaration of Helsinki under a protocol approved by the FDA and the University of Tennessee Graduate School of Medicine Institutional Review Board.…”

Section: Patientsmentioning

confidence: 99%

Radioimmunodetection of amyloid deposits in patients with AL amyloidosis

Wall¹,

Kennel²,

Stuckey³

et al. 2010

Blood

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Care of patients with AL amyloidosis currently is limited by the lack of objective means to document disease extent, as well as therapeutic options that expedite removal of pathologic deposits. To address these issues, we have initiated a Phase I Exploratory IND study to determine the biodistribution of the fibrilreactive, amyloidolytic murine IgG1 mAb 11-1F4 labeled with I-124. Patients were infused with less than 1 mg (ϳ 74 MBq) of GMP-grade antibody and imaged by PET/CT scan 48 and 120 hours later. Among 9 of 18 subjects, there was striking uptake of the reagent in liver, lymph nodes, bone marrow, intestine, or, unexpectedly, spleen (but not kidneys or heart). Generally, positive or negative results correlated with those obtained immunohistochemically using diagnostic tissue biopsy specimens. Based on these findings, we posit that 124 I-mAb m11-1F4 can be used to identify AL candidates for passive immunotherapy using the chimeric form of the antibody. This trial was registered at www.clinicaltrials.gov as NCT00807872. (Blood. 2010;116(13): 2241-2244) IntroductionLight chain-associated (AL) amyloidosis is a monoclonal plasma cell dyscrasia characterized by the pathologic deposition in vital tissues of fibrils formed from or immunoglobulin (Ig) light chain-related components. 1-3 The relentless accumulation of such fibrillar material typically leads to progressive organ dysfunction and death within 18 to 36 months. In the case of cardiac involvement, the prognosis is even more ominous, with a survival time of 3 to 9 months; fewer than 5% of all AL amyloidosis patients live more than 10 years after diagnosis. 4 Currently, therapeutic options are limited to diminishing light chain production with anti-plasma cell chemotherapy (eg, melphalan and/or corticosteroids) given in conventional amounts or high doses combined with autologous stem cell transplantation. [4][5][6][7][8][9] This approach, which is based on the premise that reduction in synthesis of the amyloidogenic precursor will slow fibril formation, has extended length of life and, in some instances, resulted in improved organ function over time; nonetheless, the prognosis remains poor because of persistent amyloid burden.To address this issue, we have focused on passive immunotherapy as a means to expedite removal of amyloid deposits and, through these research efforts, developed a murine (m) IgG1 anti-human light chain monoclonal antibody (mAb), designated 11-1F4, which recognized a conformational epitope present on amyloid fibrils, but not the soluble amyloidogenic precursor protein. 10,11 Furthermore, when administered to mice bearing subcutaneous human AL amyloidomas, the antibody bound to the pathologic material and initiated an inflammatory response that led to elimination of the induced tumors. 12 Notably, we also demonstrated that m11-1F4, after radiolabeling with the positron-emitting isotope I-124, imaged the xenograft, as evidenced by micropositron emission tomography/computed tomography (PET/CT). 13 These results have led to a Food and Drug Ad...

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Section: Patientsmentioning

confidence: 99%

Radioimmunodetection of amyloid deposits in patients with AL amyloidosis

Wall¹,

Kennel²,

Stuckey³

et al. 2010

Blood

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“…Rare samples do not react with the Freelite ™ assay [10]. There are also reports that the antisera may cross react with κ and λ light chains that are bound to heavy chains leading to overestimation of the involved FLC [12]. These analytical limitations demonstrate the need for assay improvement.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the N Latex free light chain assay in the diagnosis and monitoring of AL amyloidosis

Mollee

Tate

Pretorius

2013

Clinical Chemistry and Laboratory Medicine (CCLM)

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“…In the present case, an alternative splicing in the Vλ exon using the cryptic site TG/GTAGT in CDR1 led to the skipping of the premature stop codon and the production of truncated in-frame mRNA λ LC (Supplemental Fig.2). Since most of the Vλ domain is missing in the truncated LC, we performed a western blot using an anti-Vλ2 domain antibody 7 which proved positive for the full length polyclonal λ LC containing Vλ2 domains but failed to detect the shortened monoclonal V domain (Fig 2C).…”

Section: Sébastienmentioning

confidence: 99%