Comparative Biosciences, Inc. 786 Lucerne Drive Sunnyvale, CA 94085 Telephone: 408.738.9261 www.compbio.com A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH.

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Comparative Biosciences, Inc. 786 Lucerne Drive Sunnyvale, CA Telephone: A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH

Passive Heymann nephritis in rats resembles membranous nephropathy in man. It is induced by injection of sheep antibody to rat proximal tubular epithelial cell brush border antigen (anti-Fx1A). This is a robust and validated model at CBI. Induce with administration of optimal concentrations anti-Fx1A IgG in rats administered as a single systemic dose in CFA Urine changes-marked increases in urinary protein, creatinine and protein/creatinine ratios due to glomerular damage beginning within one week and increasing over 2-3 weeks Glomerular histologic changes of glomerular hypercellularity, inflammation and deposition visible by 3 weeks histologically Positive controls-not well understood, steroids not effective, mycophenolate mofetil show some activity

Characteristic Glomerular Lesions Glomerular hypercellularity with eosinophilic deposition, inflammation, and wire loop lesions Hyperplasia of the Bowman’s capsule Proteinic material in tubules and tubular dilation Interstitial lymphocytic inflammation A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH

Light microscopic examination Standard stains-HE, Trichrome, Sirius Red, Periodic acid Schiff, Jones methenamine silver stains Immunohistochemistry-collagen, SMA, basement membrane, inflammation Semi-quantitative assessment Option for histomorphometry A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH

Assessment by ACVP Veterinary Pathologist Entire kidney and subparts of the nephron assessed Glomerulus, mesangium, basement membrane, Bowman’s capsule, cellular infiltrates, tubules, interstitium Incidence and severity of the lesions were scored using the accepted industry scoring system of 0-4, corresponding to normal, minimal, mild, moderate, and severe, respectively. Lesions scored for duration (acute, subacute, and chronic) and distribution (focal, multifocal, diffuse) based on the composition and numbers of cell types present A TRANSLATIONAL APPROACH TO PRECLINICAL RESEARCH

Heymann Nephritis Immune mediated FX-1- induced glomerular nephritis is an established, robust, reproducible model at CBI Rats are administered the FX-1 antibody Urine changes-marked increases in urinary protein, creatinine and protein/creatinine ratios due to glomerular damage beginning within one week and increasing over 2-3 weeks Glomerular histologic changes of glomerular hypercellularity, inflammation and deposition visible by 3 weeks histologically