ImmunoPET imaging of phosphatidylserine in pro-apoptotic therapy treated tumor models.
An immunoPET imaging probe for the detection of phosphatidylserine was developed and tested in animal models of human cancer treated with pro-apoptotic therapy. We hypothesized that the relatively long plasma half-life of a probe based on a full-length antibody coupled with a residualizing radionuclide would be able to catch the wave of drug-induced apoptosis and lead to a specific accumulation in apoptotic tumor tissue.


METHODS
The imaging probe is based on a ⁸⁹Zr-labeled monoclonal antibody PGN635 targeting phosphatidylserine. The probe was evaluated pre-clinically in four tumor xenograft models: one studied treatment with paclitaxel to trigger the intrinsic apoptotic pathway, and three others interrogated treatment with an agonistic death-receptor monoclonal antibody to engage the extrinsic apoptotic pathway.


RESULTS
High accumulation of ⁸⁹Zr-PGN635 was observed in treated tumors undergoing apoptosis reaching 30 %ID/g and tumor-to-blood ratios up to 13. The tumor uptake in control groups treated with vehicle or imaged with a non-binding antibody probe was significantly lower.


CONCLUSIONS
The results demonstrate the ability of ⁸⁹Zr-PGN635 to image drug-induced apoptosis in animal models and corroborate our hypothesis that radiolabeled antibodies binding to intracellular targets transiently exposed on the cell surface during apoptosis can be employed for detection of tumor response to therapy.
Genentech Research and Early Development-gRED, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Annie
A
Ogasawara
Jeff N
JN
Tinianow
Alexander N
AN
Vanderbilt
Herman S
HS
Gill
Sharon
S
Yee
Judith E
JE
Flores
Simon-Peter
SP
Williams
Avi
A
Ashkenazi
Jan
J
Marik
D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D010718:Phosphatidylserines / Q000276:immunology* / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes; D015040:Zirconium
D000911:Antibodies, Monoclonal; D010718:Phosphatidylserines; D011868:Radioisotopes; D015040:Zirconium