Bispecific antibody pretargeting of tumor neovasculature for improved systemic radiotherapy of solid tumors.
OBJECTIVE
Extra domain B (ED-B) fibronectin is a specific tumor matrix marker for targeting angiogenesis in solid tumors. In this study, the radiotherapeutic potential of the directly radioiodinated divalent anti-ED-B antibody fragment, L19 small immunoprotein (L19-SIP; 75,000 Da), was compared with a pretargeting approach using the bispecific antibody AP39xm679 (bsMAb; 75,000 Da).


METHODS
The bsMAb was prepared by coupling an anti-ED-B single-chain Fv (AP39) to the Fab' of the murine antibody m679, which binds to the small peptidic hapten histamine-succinyl-glycine (HSG). As an effector molecule for the pretargeting approach, the 111In-labeled HSG-DOTA complex was injected 25 or 41 hours after the bsMAb. The kinetics of both the iodinated bsMAb and the pretargeted 111In-labeled HSG hapten were investigated in mice bearing human glioblastoma xenografts (U251) and compared with the kinetics and tumor accumulation of radioiodinated L19-SIP. 111In and 125I were used as surrogate marker for the therapeutic radioisotopes 90Y/177Lu and 131I, respectively.


RESULTS
Tumor uptake of the pretargeted 111In-labeled peptide was significantly higher than 125I-L19-SIP over 7 days. At the calculated maximally tolerated dose for each agent (with the kidney being the dose-limiting organ for pretargeting and the bone marrow for direct targeting), a mouse tumor dose of 146 Gy could be given by pretargeting versus 45 Gy delivered by the direct approach.


CONCLUSIONS
These data suggest that pretargeting of ED-B with AP39xm679 and subsequent injection of the 90Y-hapten-peptide would improve the therapeutic efficacy in solid tumors by >3-fold compared with directly radiolabeled 131I-L19-SIP.
Moosmayer
Dieter
D
Schering AG, Research Laboratories, Berlin, Germany. dieter.moosmayer@schering.de
Berndorff
Dietmar
D
Chang
Chien-Hsing
CH
Sharkey
Robert M
RM
Rother
Axel
A
Borkowski
Sandra
S
Rossi
Edmund A
EA
McBride
William J
WJ
Cardillo
Thomas M
TM
Goldenberg
David M
DM
Dinkelborg
Ludger M
LM
D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000032:analysis; D000951:Antigens, Neoplasm / Q000032:analysis; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005909:Glioblastoma / Q000532:radiotherapy; D006801:Humans; D007457:Iodine Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000532:radiotherapy*; D011829:Radiation Dosage; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D018033:Antibodies, Bispecific; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D007457:Iodine Radioisotopes