Targeting Topics 06q2

Safety evaluation of intrathecal substance P-saporin, a targeted neurotoxin, in dogs.

Allen JW, Mantyh PW, Horais K, Tozier N, Rogers SD, Ghilardi JR, Cizkova D, Grafe MR, Richter P, Lappi DA, Yaksh TL.

Toxicol Sci 91(1):286-298, 2006.

SP-SAP (Cat. #IT-07) has been shown to reverse neuropathic pain behavior in rodents and prevent the formation of hyperalgesia. A safety study was done in beagles to further the use of this molecule as a human therapeutic. Animals received doses from 1.5-150 µg of SP-SAP as bolus intrathecal lumbar injections. Doses of 15 µg and above displayed significant loss of NK1r-expressing cells in lumbar Laminae II and I, but no adverse toxicity was observed at any dose.

Estradiol and orexin-2 saporin actions on multiple forms of behavioral arousal in female mice.

Easton A, Dwyer E, Pfaff DW.

Behav Neurosci 120(1):1-9, 2006.

Many aspects of female behavioral arousal in response to estrogens are not yet well understood. Here the authors examine the role of orexins as targets for estrogens. Female mice were treated with 10 ng of orexin-SAP (Cat. #IT-20) into each hemisphere of the lateral hypothalamus. The mice were then tested in different modes of behavioral arousal. Mice treated with orexin-SAP displayed decreases in sensory responsiveness and fearfulness concomitant with a reduction in orexin cell number.

Prenatal glucocorticoid exposure affects learning and vulnerability of cholinergic neurons.

Emgard M, Paradisi M, Pirondi S, Fernandez M, Giardino L, Calza L.

Neurobiol Aging 28(1):112-121, 2007.

Women at risk of preterm delivery are commonly treated with synthetic glucocorticoids such as dexamethasone and betamethasone. Here the authors examined adult rats that were prenatally exposed to glucocorticoids. After 2.5 µg intracerebroventricular injections of 192-IgG-SAP (Cat. #IT-01) or 0.44 µg of saporin (Cat. #PR-01), the rats were tested in a water maze pool. The evidence suggests that not only do prenatal glucocorticoids affect adult cognitive function, they also make cholinergic neurons more susceptible to challenges later in life.

Targeting of the receptor protein tyrosine phosphatase beta with a monoclonal antibody delays tumor growth in a glioblastoma model.

Foehr ED, Lorente G, Kuo J, Ram R, Nikolich K, Urfer R.

Cancer Res 66(4):2271-2278, 2006.

The receptor protein tyrosine phosphatase ß (RPTPß) is overexpressed in astrocytomas, and is a potential target for tumor therapy. After testing antibodies against an extracellular domain of RPTPß in vitro with Mab-ZAP (Cat. #IT-04), two custom conjugates, 7E4B11-SAP and 7A9B5-SAP, were created by Advanced Targeting Systems. The authors tested the custom conjugates, using anti-DAT-SAP (Cat. #IT-25) as a positive control, and mouse IgG-SAP (Cat. #IT-18) as a negative control. The 7E4B11-SAP conjugate displayed significant antitumor activity in mice engrafted with U87 glioma cells.

Effect of N-methyl-d-aspartate receptor blockade on plasticity of frontal cortex after cholinergic deafferentation in rat.

Garrett JE, Kim I, Wilson RE, Wellman CL.

Neuroscience 140(1):57-66, 2006.

Acetylcholine from the nucleus basalis magnocellularis (NBM) plays roles in neocortical function and plasticity. Here the authors examined whether N-methyl-D-aspartate receptors mediate the increase in the GluR1 subunit of the α-amino-3-hydroxy-5-methylisoxazole-4-proprionate receptor in the frontal cortex following treatment of the NBM with 0.15 µg of 192-IgG-SAP (Cat. #IT-01). The data indicates that upregulation of GluR1 and spine density after cholinergic deafferentation is regulated by N-methyl-D-aspartate receptors.

Catecholamine neurones in rats modulate sleep, breathing, central chemoreception and breathing variability.

Li A, Nattie E.

J Physiol 570(Pt 2):385-396, 2006.

Brainstem catecholamine (CA) neurons are thought to modulate the processing of sensory information and participate in the control of breathing. Using a 5 µg injection of anti-DBH-SAP (Cat. #IT-03), or a control injection of mouse-IgG-SAP (Cat. #IT-18) into the fourth ventricle, the authors investigated breathing frequency and wakefulness. The results suggest that CA neurons promote wakefulness, participate in central respiratory chemoreception, stimulate breathing frequency, and minimize breathing variability during REM sleep.

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF-saporin.

Weyergang A, Selbo PK, Berg K.

J Control Release 111(1-2):165-173, 2006.

In this study the authors investigated the use of photosensitizers located in endocytic vesicles that can be induced to release macromolecules upon activation by light. This process is called photochemical internalization, or PCI. Biotinylated EGF was combined with streptavidin-ZAP (Cat. #IT-27), and the compound was applied to various cell lines. The data shows that PCI increases the toxicity of EGF-saporin significantly in EGF receptor-expressing cell lines.