Publications (6) View all
-
Article: Generation and characterization of anti-AA amyloid-specific monoclonal antibodies.
[show abstract] [hide abstract]
ABSTRACT: AA amyloidosis results from the pathologic deposition in the kidneys and other organs of fibrils composed of N-terminal fragments of serum amyloid A protein (SAA). Given that there are only limited means to visualize these deposits, we have developed a series of mAbs, 2A4, 7D8, and 8G9, that bind specifically with nanomolar affinity to a carboxy-terminal epitope generated following proteolysis of SAA that yields the predominant component of AA amyloid deposits. Notably, these antibodies do not recognize native SAA, they retain their immunoreactivity when radiolabeled with I-125 and, after injection into AA amyloidotic mice, localize, as evidenced by autoradiography and micro-single photon emission computed tomography imaging, to histologically confirmed areas of amyloid deposition; namely, spleen, liver, and pancreas. The results of our in vitro and in vivo studies demonstrate the AA fibril-selectivity of mAbs 2A4, 7D8, and 8G9 and warrant further investigation into their role as novel diagnostic agents for patients with AA amyloidosis.Frontiers in immunology. 01/2011; 2:32. -
Article: Splenic plasma cells can serve as a source of amyloidogenic light chains.
[show abstract] [hide abstract]
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 kappa and lambda, and anti-V(L) subgroup-specific monoclonal antibodies (mAbs). In 12 cases, there was statistically significant evidence of a monoclonal population bearing the same kappa or lambda 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.Blood 01/2009; 113(7):1501-3. · 9.90 Impact Factor -
Article: Immunodiagnostic capabilities of anti-free immunoglobulin light chain monoclonal antibodies.
[show abstract] [hide abstract]
ABSTRACT: Overproduction of plasma cell-derived monoclonal free kappa or lambda immunoglobulin light chains (FLCs) is a hallmark of multiple myeloma, AL amyloidosis, and light chain deposition disease. Because these components serve as unique cellular and serologic biomarkers, their detection and quantitation has diagnostic, therapeutic, and prognostic import. In this regard, we have developed monoclonal antibodies (mAbs) that specifically recognize the kappa or lambda FLC products of all known human variable and constant region light chain genes. We now report the results of our studies that have demonstrated the capability of these reagents to measure, in a modified fluid-phase capture enzyme-linked immunosorbent assay (ELISA), serum kappa and lambda FLCs at concentrations as low as 5 and 15 ng/mL, respectively. The mAb-based ELISA has greater sensitivity and reproducibility than does the commercially available immunoturbidimetric assay that uses polyclonal anti-FLC antibodies. In addition, the mAbs can immunostain monoclonal FLC-producing plasma cells and pathologic light chain-related amyloid and nonfibrillar tissue deposits. Our anti-FLC mAbs, with their high degree of reactivity and versatility, may provide an invaluable tool in the diagnosis and management of light chain-associated disease.American Journal of Clinical Pathology 12/2008; 130(5):702-11. · 2.60 Impact Factor -
Article: Odontogenic ameloblast-associated protein nature of the amyloid found in calcifying epithelial odontogenic tumors and unerupted tooth follicles.
[show abstract] [hide abstract]
ABSTRACT: We have previously reported that the amyloid found in three patients with calcifying epithelial odontogenic tumors (CEOT) was composed of N-terminal fragments of a putative 153-residue protein specified by a gene designated FLJ20513 now known to represent exons 5 through 10 of the odontogenic ameloblast-associated protein (ODAM) locus that encodes a 279-residue polypeptide. Confirmation of the amyloidogenic potential of ODAM has resulted from analyses of four other cases where we found, in addition, a 74-residue segment specified by exon 4. Through preparation of ODAM-related synthetic peptides, it was possible to localize the fibril-forming region of this molecule, as well as generate a monoclonal antibody that reacted specifically with the amyloid associated with CEOT. Notably, we also detected green birefringent congophilic material in unerupted tooth follicles - a precursor of CEOT - and demonstrated through immunologic and chemical analyses the ODAM nature of the deposits. Our studies have provided further evidence for this unique form of odontogenic amyloid that we provisionally designate "AODAM".Amyloid: the international journal of experimental and clinical investigation: the official journal of the International Society of Amyloidosis 07/2008; 15(2):89-95. · 2.12 Impact Factor -
Article: Identification of an antilaminin-1 scFv that preferentially homes to vascular solid tumors.
[show abstract] [hide abstract]
ABSTRACT: The tumor vasculature and extracellular matrix make attractive targets for distinguishing solid tumors from normal cells. In solid tumors, the processes of angiogenesis and metastasis potentially give rise to unique epitopes not usually accessible in homeostatic organs. Specific targeting of solid tumors for radioimmunotherapy requires that the targeting agent accumulate rapidly and at high levels at the tumor site. This study involved the selection of scFvs that recognize laminin-1 in vitro from the Tomlinson I and J phage display libraries. Selected, purified scFvs were radioiodinated and injected in tumor-bearing mice. One of these, scFv 15-9, exhibited preferential accumulation at subcutaneous tumors when compared to other antilaminin scFvs or to a control scFv. Autoradiographic analysis indicated that scFv15- 9 also displayed a higher vessel:parenchyma ratio than did two other antilaminin scFvs, scFv 15-6 and scFv 15-1, indicating a preferential accumulation of scFv 15-9 around vessel structures. Immunohistochemistry confirmed that scFv 15-9 accumulated at sites of endothelial cells lining vessel structures where significant levels of laminin were present. These data demonstrate that scFv 15-9 binds to a specific epitope on laminin and has potential for tumor endoradiotherapy in subcutaneous tumors.Cancer Biotherapy and Radiopharmaceuticals 11/2005; 20(5):524-33. · 1.79 Impact Factor
