Kirstin A Zettlitz1,2,3, Wen-Ting K Tsai4,5, Scott M Knowles4,5,6, Felix B Salazar4,5, Naoko Kobayashi5,7, Robert E Reiter5,7, Anna M Wu4,5,8. 1. Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. kzettlitz@coh.org. 2. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. kzettlitz@coh.org. 3. Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA. kzettlitz@coh.org. 4. Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA. 5. David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. 6. University of Washington/Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N-D5-100, Seattle, WA, 98109, USA. 7. Department of Urology, University of California Los Angeles, Los Angeles, CA, USA. 8. Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA.
Abstract
PURPOSE: A great challenge in the diagnosis and treatment of prostate cancer is distinguishing between indolent or local disease and aggressive or metastatic disease. Antibody-based positron emission tomography (immuno-PET) as a cancer-specific imaging modality could improve diagnosis of primary disease, aid the detection of metastases to regional lymph nodes as well as to distant sites (e.g., bone), and monitor response to therapy. PROCEDURE: In search for a more physiologically relevant disease model, a human prostate stem cell antigen knock-in (hPSCA KI) mouse model was generated. The use of a syngeneic prostate cancer cell line transduced to express human PSCA (RM-9-hPSCA) enabled the evaluation of anti-PSCA immuno-PET in immunocompetent mice and in the context of normal tissue expression of PSCA. Two PSCA-specific humanized antibody fragments, A11 minibody and A2 cys-diabody, were radiolabeled with positron emitters iodine-124 and zirconium-89, respectively ([124I]A11 Mb and [89Zr]A2cDb), and used for immuno-PET in wild-type, hPSCA KI and tumor-bearing mice. RESULTS: The hPSCA KI mice express PSCA at low levels in the normal prostate, bladder and stomach, reproducing the expression pattern seen in humans. [124I]A11 Mb immuno-PET detected increased levels of PSCA expression in the stomach, and because I-124 is non-residualizing, very little activity was seen in organs of clearance (liver, kidney, spleen). However, due to the longer half-life of the 80 kDa protein, blood activity (and thus urine activity) at 20 h postinjection remains high. The smaller 50 kDa [89Zr]A2cDb cleared faster, resulting in lower blood and background activity, despite the use of a residualizing radiometal. Importantly, [89Zr]A2cDb immuno-PET showed antigen-specific targeting of PSCA-expressing tumors and minimal nonspecific uptake in PSCA-negative controls. CONCLUSION: Tracer biodistribution was not significantly impacted by normal tissue expression of PSCA. [89Zr]A2cDb immuno-PET yielded high tumor-to-blood ratio at early time points. Rapid renal clearance of the 50 kDa tracer resulted in an unobstructed view of the pelvic region at 20 h postinjection that would allow the detection of cancer in the prostate.
PURPOSE: A great challenge in the diagnosis and treatment of prostate cancer is distinguishing between indolent or local disease and aggressive or metastatic disease. Antibody-based positron emission tomography (immuno-PET) as a cancer-specific imaging modality could improve diagnosis of primary disease, aid the detection of metastases to regional lymph nodes as well as to distant sites (e.g., bone), and monitor response to therapy. PROCEDURE: In search for a more physiologically relevant disease model, a humanprostate stem cell antigen knock-in (hPSCA KI) mouse model was generated. The use of a syngeneic prostate cancer cell line transduced to express humanPSCA (RM-9-hPSCA) enabled the evaluation of anti-PSCA immuno-PET in immunocompetent mice and in the context of normal tissue expression of PSCA. Two PSCA-specific humanized antibody fragments, A11 minibody and A2 cys-diabody, were radiolabeled with positron emitters iodine-124 and zirconium-89, respectively ([124I]A11 Mb and [89Zr]A2cDb), and used for immuno-PET in wild-type, hPSCA KI and tumor-bearing mice. RESULTS: The hPSCA KI mice express PSCA at low levels in the normal prostate, bladder and stomach, reproducing the expression pattern seen in humans. [124I]A11 Mb immuno-PET detected increased levels of PSCA expression in the stomach, and because I-124 is non-residualizing, very little activity was seen in organs of clearance (liver, kidney, spleen). However, due to the longer half-life of the 80 kDa protein, blood activity (and thus urine activity) at 20 h postinjection remains high. The smaller 50 kDa [89Zr]A2cDb cleared faster, resulting in lower blood and background activity, despite the use of a residualizing radiometal. Importantly, [89Zr]A2cDb immuno-PET showed antigen-specific targeting of PSCA-expressing tumors and minimal nonspecific uptake in PSCA-negative controls. CONCLUSION: Tracer biodistribution was not significantly impacted by normal tissue expression of PSCA. [89Zr]A2cDb immuno-PET yielded high tumor-to-blood ratio at early time points. Rapid renal clearance of the 50 kDa tracer resulted in an unobstructed view of the pelvic region at 20 h postinjection that would allow the detection of cancer in the prostate.
Authors: Scott M Knowles; Kirstin A Zettlitz; Richard Tavaré; Matthew M Rochefort; Felix B Salazar; David B Stout; Paul J Yazaki; Robert E Reiter; Anna M Wu Journal: J Nucl Med Date: 2014-02-06 Impact factor: 10.057
Authors: Sai Kiran Sharma; Andrew Chow; Sebastien Monette; Delphine Vivier; Jacob Pourat; Kimberly J Edwards; Thomas R Dilling; Dalya Abdel-Atti; Brian M Zeglis; John T Poirier; Jason S Lewis Journal: Cancer Res Date: 2018-01-23 Impact factor: 12.701
Authors: Z Gu; G Thomas; J Yamashiro; I P Shintaku; F Dorey; A Raitano; O N Witte; J W Said; M Loda; R E Reiter Journal: Oncogene Date: 2000-03-02 Impact factor: 9.867
Authors: Tove Olafsen; Zhennan Gu; Mark A Sherman; Jeffrey V Leyton; Michael E Witkosky; John E Shively; Andrew A Raubitschek; Sherie L Morrison; Anna M Wu; Robert E Reiter Journal: J Immunother Date: 2007 May-Jun Impact factor: 4.456
Authors: Mo Zhang; Naoko Kobayashi; Kirstin A Zettlitz; Evelyn A Kono; Joyce M Yamashiro; Wen-Ting K Tsai; Ziyue K Jiang; Chau P Tran; Chung Wang; Johnny Guan; Anna M Wu; Robert E Reiter Journal: Clin Cancer Res Date: 2018-10-09 Impact factor: 12.531
Authors: Wenting K Tsai; Kirstin A Zettlitz; Richard Tavaré; Naoko Kobayashi; Robert E Reiter; Anna M Wu Journal: Theranostics Date: 2018-11-12 Impact factor: 11.556