Zettlitz Kirstin A, Tsai Wen-Ting K, Knowles Scott M, Salazar Felix B, Kobayashi Naoko, Reiter Robert E, Wu Anna M
Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA.
David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Mol Imaging Biol. 2020 Apr;22(2):367-376. doi: 10.1007/s11307-019-01386-7.
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.
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 ([I]A11 Mb and [Zr]A2cDb), and used for immuno-PET in wild-type, hPSCA KI and tumor-bearing mice.
The hPSCA KI mice express PSCA at low levels in the normal prostate, bladder and stomach, reproducing the expression pattern seen in humans. [I]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 [Zr]A2cDb cleared faster, resulting in lower blood and background activity, despite the use of a residualizing radiometal. Importantly, [Zr]A2cDb immuno-PET showed antigen-specific targeting of PSCA-expressing tumors and minimal nonspecific uptake in PSCA-negative controls.
Tracer biodistribution was not significantly impacted by normal tissue expression of PSCA. [Zr]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.
前列腺癌诊断与治疗中的一大挑战是区分惰性或局部疾病与侵袭性或转移性疾病。基于抗体的正电子发射断层扫描（免疫PET）作为一种癌症特异性成像方式，可改善原发性疾病的诊断，有助于检测区域淋巴结以及远处部位（如骨骼）的转移灶，并监测治疗反应。
为了寻找更具生理相关性的疾病模型，构建了人前列腺干细胞抗原敲入（hPSCA KI）小鼠模型。使用转导表达人PSCA的同基因前列腺癌细胞系（RM-9-hPSCA），能够在免疫活性小鼠以及PSCA正常组织表达的背景下评估抗PSCA免疫PET。分别用正电子发射体碘-124和锆-89对两种PSCA特异性人源化抗体片段A11微抗体和A2半胱氨酸双抗体进行放射性标记（[I]A11 Mb和[Zr]A2cDb），并用于野生型、hPSCA KI和荷瘤小鼠的免疫PET研究。
hPSCA KI小鼠在正常前列腺、膀胱和胃中低水平表达PSCA，重现了人类的表达模式。[I]A11 Mb免疫PET检测到胃中PSCA表达水平升高，并且由于I-124不具有残留性，在清除器官（肝脏、肾脏、脾脏）中几乎未见活性。然而，由于80 kDa蛋白的半衰期较长，注射后20小时血液活性（进而尿液活性）仍然较高。尽管使用了具有残留性的放射性金属，但较小的50 kDa [Zr]A2cDb清除更快，导致血液和背景活性较低。重要的是，[Zr]A2cDb免疫PET显示了对表达PSCA的肿瘤的抗原特异性靶向，并且在PSCA阴性对照中无特异性摄取。
PSCA的正常组织表达对示踪剂生物分布没有显著影响。[Zr]A2cDb免疫PET在早期时间点产生了高肿瘤与血液比值。50 kDa示踪剂的快速肾脏清除导致注射后20小时盆腔区域视野清晰，这将有助于检测前列腺中的癌症。
