Peripheral and Central Nervous System Distribution of a CGRP Neutralizing Antibody [125I]-LY2951742 in Male Rats (S26.007)

Objective: To characterize the relative distribution of a calcitonin gene-related peptide (CGRP) neutralizing antibody into peripheral and central nervous system tissues. Background: Recent clinical studies have shown that CGRP neutralizing antibodies such as LY2951742 are efficacious for migraine prevention. As such, the distribution of LY2951742 into peripheral and central tissues was determined to characterize potential sites of action. In order to determine this experimentally, radiolabelled CGRP neutralizing antibody (LY2951742) and a control IgG4 antibody were injected and their biodistribution measured. Methods: LY2951742 and a control IgG4 antibody were radioiodinated to give specific activities of 0.11 mCi/mg and 0.16 mCi/mg, respectively. At 24, 72 and 168 hours following subcutaneous injection of either antibody (4 mg/kg), cerebrospinal fluid (CSF) and plasma were collected, followed by whole body perfusion to remove residual blood and dissection of selected tissues for quantitation of wet weight and [ 125 I] present. Results: The peak plasma levels of both [ 125 I]LY2951742 and [ 125 I]control IgG4 were observed at 72 hours and remained high at 168 hours post-dose. No significant differences in distribution were seen for [ 125 I]LY2951742 versus [ 125 I]IgG4 control. The rank order of tissue levels was: dura mater = spleen > trigeminal ganglia >> hypothalamus = spinal cord = prefrontal cortex = cerebellum = CSF. [ 125 I]LY2951742 peripheral tissue levels (dura mater, spleen and trigeminal ganglia) averaged 4-11[percnt] of plasma while all of the CNS tissues had levels that were <0.4[percnt] of plasma. Conclusions: Distribution of the antibodies into the dura mater and the trigeminal ganglia was similar to that observed in the spleen, and significantly greater than exposure in the brain or spinal cord. Although the central levels of LY2951742 were relatively low, a central site of action for the observed clinical efficacy cannot be excluded. Disclosure: Dr. Johnson has received personal compensation for activities with Eli Lilly & Company. Dr. Ellis has received personal compensation for activities with Eli Lilly & Company. Dr. Maren has received personal compensation for activities with Eli Lilly & Company. Dr. Morin has received personal compensation for activities with Eli Lilly & Company. Dr. Wroblewski has received personal compensation for activities with Eli Lilly & Company. Dr. Johnson has received personal compensation for activities with Eli Lilly & Company.