Molecular targeting and treatment of composite EGFR and EGFRvIII-positive gliomas using boronated monoclonal antibodies.
OBJECTIVE
The purpose of the present study was to evaluate the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), cetuximab, (IMC-C225) and the anti-EGFRvIII mAb, L8A4, used in combination as delivery agents for boron neutron capture therapy (BNCT) of a rat glioma composed of a mixture of cells expressing either wild-type (F98(EGFR)) or mutant receptors(F98(npEGFRvIII)).


METHODS
A heavily boronated polyamidoamine dendrimer (BD) was linked by heterobifunctional reagents to produce the boronated mAbs, BD-C225 and BD-L8A4. For in vivo biodistribution and therapy studies, a mixture of tumor cells were implanted intracerebrally into Fischer rats. Biodistribution studies were carried out by administering (125)I-labeled bioconjugates via convection-enhanced delivery (CED), and for therapy studies, nonradiolabeled bioconjugates were used for BNCT. This was carried out 14 days after tumor implantation and 24 h after CED at the Massachusetts Institute of Technology nuclear reactor.


RESULTS
Following CED of a mixture of (125)I-BD-C225 and (125)I-BD-L8A4 to rats bearing composite tumors, 61.4% of the injected dose per gram (ID/g) was localized in the tumor compared with 30.8% ID/g for (125)I-BD-L8A4 and 34.7% ID/g for (125)I-BD-C225 alone. The corresponding calculated tumor boron values were 24.4 mug/g for rats that received both mAbs, and 12.3 and 13.8 mug/g, respectively, for BD-L8A4 or BD-C225 alone. The mean survival time of animals bearing composite tumors, which received both mAbs, was 55 days (P < 0.0001) compared with 36 days for BD-L8A4 and 38 days for BD-C225 alone, which were not significantly different from irradiated controls.


CONCLUSIONS
Both EGFRvIII and wild-type EGFR tumor cell populations must be targeted using a combination of BD-cetuximab and BD-L8A4. Although in vitro C225 recognized both receptors, in vivo it was incapable of delivering the requisite amount of (10)B for BNCT of EGFRvIII-expressing gliomas.
Yang
Weilian
W
Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA.
Wu
Gong
G
Barth
Rolf F
RF
Swindall
Michele R
MR
Bandyopadhyaya
Achintya K
AK
Tjarks
Werner
W
Tordoff
Kevin
K
Moeschberger
Melvin
M
Sferra
Thomas J
TJ
Binns
Peter J
PJ
Riley
Kent J
KJ
Ciesielski
Michael J
MJ
Fenstermaker
Robert A
RA
Wikstrand
Carol J
CJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001666:Binding Sites, Antibody; D001895:Boron / Q000032:analysis* / Q000276:immunology; D001932:Brain Neoplasms / Q000532:radiotherapy*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000032:analysis*; D005910:Glioma / Q000532:radiotherapy*
D000911:Antibodies, Monoclonal; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D001895:Boron