Burvenich, Ingrid J G; Parakh, Sagun; Gan, Hui K; Lee, Fook-Thean; Guo, Nancy; Rigopoulos, Angela; Lee, Sze-Ting; Gong, Sylvia; O'Keefe, Graeme J; Tochon-Danguy, Henri; Kotsuma, Masakatsu; Hasegawa, Jun; Senaldi, Giorgio; Scott, Andrew M

doi:10.2967/jnumed.115.169839

Author(s)

Burvenich, Ingrid J G

Parakh, Sagun

Gan, Hui K

Lee, Fook-Thean

Guo, Nancy

Rigopoulos, Angela

Lee, Sze-Ting

Gong, Sylvia

O'Keefe, Graeme J

Tochon-Danguy, Henri

Kotsuma, Masakatsu

Hasegawa, Jun

Senaldi, Giorgio

Scott, Andrew M

Publication Date

2016-06

Abstract

Subtype A2 of the erythropoietin-producing hepatocellular tyrosine kinase (EphA2) cell surface receptor is expressed in a range of epithelial cancers. This study evaluated the molecular imaging of EphA2 expression in vivo in mouse tumor models using SPECT/MR and PET/MR and a humanized anti-EphA2 antibody, DS-8895a. DS-8895a was labeled with (111)In, (125)I, and (89)Zr and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen-binding affinity (Scatchard analysis), and serum stability in vitro. In vivo biodistribution, imaging, and pharmacokinetic studies were performed with SPECT/MR and PET/MR. A dose-escalation study was also performed to determine EphA2 receptor saturability through tissue and imaging quantitative analysis. All conjugates demonstrated good serum stability and specific binding to EphA2-expressing cells in vitro. In vivo biodistribution studies showed high uptake of (111)In-CHX-A″-DTPA-DS-8895a and (89)Zr-Df-Bz-NCS-DS-8895a in EphA2-expressing xenograft models, with no specific uptake in normal tissues. In comparison, retention of (125)I-DS-8895a in tumors was lower because of internalization of the radioconjugate and dehalogenation. These results were confirmed by SPECT/MR and PET/MR. EphA2 receptor saturation was observed at the 30 mg/kg dose. Molecular imaging of tumor uptake of DS-8895a allows noninvasive measurement of EphA2 expression in tumors in vivo and determination of receptor saturation. (89)Zr-Df-Bz-NCS-DS-8895a is suited for human bioimaging trials on the basis of superior imaging characteristics and will inform DS-8895a dose assessment and patient response evaluation in clinical trials.

Citation

Journal of Nuclear Medicine 2016; 57(6): 974-980

Jornal Title

Journal of Nuclear Medicine

OrcId

0000-0003-3891-2489

0000-0002-6656-295X

Link

https://ahro.austin.org.au/austinjspui/handle/1/19226

Subject

89Zr

DS-8895a

EphA2

bioimaging

Cancer

Title

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with 89Zr-DS-8895a.

Type of document

Journal Article

Austin Health

Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with 89Zr-DS-8895a.

Files:

Author(s)	Burvenich, Ingrid J G Parakh, Sagun Gan, Hui K Lee, Fook-Thean Guo, Nancy Rigopoulos, Angela Lee, Sze-Ting Gong, Sylvia O'Keefe, Graeme J Tochon-Danguy, Henri Kotsuma, Masakatsu Hasegawa, Jun Senaldi, Giorgio Scott, Andrew M
Publication Date	2016-06
Abstract	Subtype A2 of the erythropoietin-producing hepatocellular tyrosine kinase (EphA2) cell surface receptor is expressed in a range of epithelial cancers. This study evaluated the molecular imaging of EphA2 expression in vivo in mouse tumor models using SPECT/MR and PET/MR and a humanized anti-EphA2 antibody, DS-8895a. DS-8895a was labeled with (111)In, (125)I, and (89)Zr and assessed for radiochemical purity, immunoreactivity (Lindmo analysis), antigen-binding affinity (Scatchard analysis), and serum stability in vitro. In vivo biodistribution, imaging, and pharmacokinetic studies were performed with SPECT/MR and PET/MR. A dose-escalation study was also performed to determine EphA2 receptor saturability through tissue and imaging quantitative analysis. All conjugates demonstrated good serum stability and specific binding to EphA2-expressing cells in vitro. In vivo biodistribution studies showed high uptake of (111)In-CHX-A″-DTPA-DS-8895a and (89)Zr-Df-Bz-NCS-DS-8895a in EphA2-expressing xenograft models, with no specific uptake in normal tissues. In comparison, retention of (125)I-DS-8895a in tumors was lower because of internalization of the radioconjugate and dehalogenation. These results were confirmed by SPECT/MR and PET/MR. EphA2 receptor saturation was observed at the 30 mg/kg dose. Molecular imaging of tumor uptake of DS-8895a allows noninvasive measurement of EphA2 expression in tumors in vivo and determination of receptor saturation. (89)Zr-Df-Bz-NCS-DS-8895a is suited for human bioimaging trials on the basis of superior imaging characteristics and will inform DS-8895a dose assessment and patient response evaluation in clinical trials.
Citation	Journal of Nuclear Medicine 2016; 57(6): 974-980
Jornal Title	Journal of Nuclear Medicine
OrcId	0000-0003-3891-2489 0000-0002-6656-295X
Link	https://ahro.austin.org.au/austinjspui/handle/1/19226
Subject	89Zr DS-8895a EphA2 bioimaging Cancer
Title	Molecular Imaging and Quantitation of EphA2 Expression in Xenograft Models with 89Zr-DS-8895a.
Type of document	Journal Article