An Analysis Of Novel Antibody Repertoires In Patients With Multiple Sclerosis: Do Particular Antibody Genes Recognize Gray Matter Cellular Targets? (P6.157)

Objective: Our goal for this project was to identify the antigens that antibodies expressed by B cells from multiple sclerosis (MS) patients react against. Background: Previous data generated from our lab on the antibody genetics has led to the recognition that patterns of mutation accumulation in the antibody genes of B cells in the central nervous system (CNS) of MS patients are unique and can be used to predict clinically isolated syndrome (CIS) conversion to MS with 94% accuracy. This Antibody Gene Signature (AGS) represents a set of novel, potentially diagnostic biomarker that is currently in clinical trials (http://www.prnewswire.com/news-releases/diogenix-msprecise-identifies-early-stage-patients-with-multiple-sclerosis-177841251.html) and provides a method to categorize patients early in their disease course in order to provide prompt treatment and prevent extensive CNS damage. Methods: We cloned and expressed more than 30 recombinant human antibodies (rhAbs) that contain the MS-AGS mutations from single cerebrospinal fluid derived B cells isolated from patients with clinically definite MS, patients with one attack of optic neuritis and patients with one attack of transverse myelitis, and tested their capacity to bind to brain tissue. Results: We found that these MS-AGS enriched antibodies from both established MS patients and patients at high risk to develop MS, bind to human and mouse brain gray matter tissue with high specificity, but do not bind to human or mouse brain white matter tissue. Confocal microscopy confirms that neurons and astrocytes in the brain gray matter tissue are recognized by these antibodies. Some of these antibodies recognize both neurons and astrocytes in the gray matter, whereas others are specific for a single cell type. Conclusions: We hypothesize that AGS-enriched rhAbs and B cells expressing these antibodies could be participating in gray matter disease pathology in both early CIS and later MS stages. Study Supported By: National MS Society and DioGenix Disclosure: Dr. Ligocki has nothing to disclose. Dr. Rounds has nothing to disclose. Dr. Li has nothing to disclose. Dr. Henson has nothing to disclose. Dr. Graves has received personal compensation for activities with Teva Neuroscience, Novartis, Pfizer Inc., and Bayer Pharmaceuticals Corp. Dr. Frohman has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Acorda, Novartis, Astellas, and Abbott. Dr. Stowe has nothing to disclose. Dr. Rivas has nothing to disclose. Dr. Guzman has nothing to disclose. Dr. Ward has nothing to disclose. Dr. Greenberg has received personal compensation for activities with Chugai, GlaxoSmithKline, Inc., Sanofi-Aventis, Diogenix, Biogen Idec, Amplimmune, Acorda, and MSAA. Dr. Greenberg has received personal compensation in an editorial capacity for JAMA Neurology. Dr. Greenberg holds stock and/or stock options in DioGenix, Inc, which sponsored research in which Dr. Greenberg was involved as an investigator. Dr. Greenberg has received research support from Guthy-Jackson Charitable Foundation, Accelerated Cure Project, and Biogen Idec. Dr. Monsonhas received personal compensation from Genentech, Inc. and Medimmune. Dr. Monson has received research support from DioGenix, Inc.