Diagnostic and therapeutic potential of amyloid-reactive IgG antibodies contained in human sera.
Passive immunotherapy using fibril-reactive mAbs has been shown experimentally to reduce amyloid formation and also accelerate amyloidolysis. We now report that human sera, as well as various sources of pooled human IgG, including pharmacologic formulations of immune globulin i.v. (IGIV), contain Abs that specifically recognize fibrils formed from light chains and other amyloidogenic precursor proteins, including serum amyloid A, transthyretin, islet amyloid polypeptide, and amyloid beta 1-40 peptide, but notably, do not react with these molecules in their native nonfibrillar forms. After isolation of the Abs from IGIV via fibril-conjugated affinity column chromatography, the EC50-binding value for light chains and amyloid beta 1-40 peptide fibrils was approximately 15 nM-a magnitude approximately 200 and 70 times less than that of the unbound fraction and unfractionated product, respectively. Comparable reactivity was found in the case of those formed from serum amyloid A, transthyretin, and islet amyloid polypeptide. The purified Abs immunostained human amyloid tissue deposits and could inhibit fibrillogenesis, as shown in fibril formation and extension assays. Most importantly, in vivo reactivity was evidenced in a murine model when the enriched Abs were used to image amyloid, as well as expedite its removal. These promising experimental results suggest that fibril affinity-purified IGIV has potential as a diagnostic and therapeutic agent for patients with amyloid-associated disease.
O'Nuallain
Brian
B
Human Immunology and Cancer Program, Department of Medicine, University of Tennessee Center for Health Science, College of Medicine, Knoxville, TN 37920, USA.
Hrncic
Rudi
R
Wall
Jonathan S
JS
Weiss
Deborah T
DT
Solomon
Alan
A
D000682:Amyloid / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D000686:Amyloidosis / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007106:Immune Sera / Q000378:metabolism*; D007074:Immunoglobulin G / Q000097:blood / Q000302:isolation & purification / Q000627:therapeutic use*; D007136:Immunoglobulins / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011228:Prealbumin / Q000276:immunology / Q000378:metabolism
D000682:Amyloid; D007106:Immune Sera; D007074:Immunoglobulin G; D007136:Immunoglobulins; D011228:Prealbumin; C035222:amyloid protein AL; C076571:transthyretin-related amyloid fibril protein, human