Intraparenchymal and intratumoral interstitial infusion of anti-glioma monoclonal antibody 8H9.
OBJECTIVE
Interstitial infusion, a form of local delivery that bypasses the blood-brain barrier, has been shown to afford high regional concentrations of a therapeutic molecule while avoiding systemic exposure. The distribution of monoclonal antibodies administered via interstitial infusion has not been characterized, and this is salient in light of the potential sequestration by epitopes expressed by targeted tissue. Interstitial delivery of murine immunoglobulin G1 monoclonal antibody (MAb) 8H9 was investigated in a rodent model for the potential treatment of infiltrative gliomas.


METHODS
MAb 8H9 was infused in varying concentrations and volumes into previously untreated animals and into an immunoreactive U87 xenograft to evaluate distributive potential. Previously untreated animals and athymic rats bearing U87 xenografts underwent variable infusions into the striatum or grafted tumor, respectively. Animals were sacrificed at multiple time points, and the volume of 8H9 distribution was determined using a new semiautomated technique.


RESULTS
Increasing both the volume and dose of 8H9 infusion increased the volume of distribution. Distribution was significantly greater at 24 hours after infusion than at 1 hour. Interstitial infusion of MAb 8H9 resulted in a positive relationship between the volume of distribution and either the infusion volume or infusion dose. No significant difference in the volume of distribution was seen between antibodies in naïve striatum and U87 xenografts. Antibody distribution was effectively augmented by convection and diffusion after delivery.


CONCLUSIONS
Finally, intratumoral interstitial infusion of a reactive MAb has been performed similarly to delivery to a normal brain. This finding is encouraging from a therapeutic standpoint, given the clinical need to affect large domains of these infiltrative tumors.
Luther
Neal
N
Department of Neurological Surgery, Weill Cornell Medical College, New York, New York 10021, USA.
Cheung
Nai-Kong V
NK
Dunkel
Ira J
IJ
Fraser
Justin F
JF
Edgar
Mark A
MA
Gutin
Philip H
PH
Souweidane
Mark M
MM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D003342:Corpus Striatum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005910:Glioma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D036502:Infusions, Intralesional / Q000379:methods*; D008657:Metabolic Clearance Rate; D051381:Rats; D011923:Rats, Nude; D014018:Tissue Distribution; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents