Selective alpha-particle mediated depletion of tumor vasculature with vascular normalization.
BACKGROUND
Abnormal regulation of angiogenesis in tumors results in the formation of vessels that are necessary for tumor growth, but compromised in structure and function. Abnormal tumor vasculature impairs oxygen and drug delivery and results in radiotherapy and chemotherapy resistance, respectively. Alpha particles are extraordinarily potent, short-ranged radiations with geometry uniquely suitable for selectively killing neovasculature.


RESULTS
Actinium-225 ((225)Ac)-E4G10, an alpha-emitting antibody construct reactive with the unengaged form of vascular endothelial cadherin, is capable of potent, selective killing of tumor neovascular endothelium and late endothelial progenitors in bone-marrow and blood. No specific normal-tissue uptake of E4G10 was seen by imaging or post-mortem biodistribution studies in mice. In a mouse-model of prostatic carcinoma, (225)Ac-E4G10 treatment resulted in inhibition of tumor growth, lower serum prostate specific antigen level and markedly prolonged survival, which was further enhanced by subsequent administration of paclitaxel. Immunohistochemistry revealed lower vessel density and enhanced tumor cell apoptosis in (225)Ac-E4G10 treated tumors. Additionally, the residual tumor vasculature appeared normalized as evident by enhanced pericyte coverage following (225)Ac-E4G10 therapy. However, no toxicity was observed in vascularized normal organs following (225)Ac-E4G10 therapy.


CONCLUSIONS
The data suggest that alpha-particle immunotherapy to neovasculature, alone or in combination with sequential chemotherapy, is an effective approach to cancer therapy.
Singh Jaggi
Jaspreet
J
Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Henke
Erik
E
Seshan
Surya V
SV
Kappel
Barry J
BJ
Chattopadhyay
Debjit
D
May
Chad
C
McDevitt
Michael R
MR
Nolan
Daniel
D
Mittal
Vivek
V
Benezra
Robert
R
Scheinberg
David A
DA
D000186:Actinium / Q000627:therapeutic use; D000512:Alpha Particles / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000528:radiation effects; D015902:Gamma Cameras; D007205:Indium Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control* / Q000532:radiotherapy; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000473:pathology; D014018:Tissue Distribution
D007205:Indium Radioisotopes; D000186:Actinium