Vilhelmsson Timmermand Oskar, Safi Marcella, Holmqvist Bo, Strand Joanna
Department of Oncology, Lund University Lund, Sweden.
ImaGene-iT AB, Medicon Village Lund, Sweden.
Am J Nucl Med Mol Imaging. 2023 Aug 15;13(4):147-155. eCollection 2023.
We have previously investigated the biodistribution and therapy effect of a humanized monoclonal antibody targeting free prostate-specific antigen (fPSA) intended for theranostics of hormone-refractory prostate cancer. In the present study, we evaluated the off-target effect and different linear energy transfer (LET) radionuclides without the effect of PSA targeting by using an antibody with the same scaffold as previously used immunoconjugates but with random, non-specific, antigen binding region. This allows us to identify alterations generated by specific targeting and those related to passive bystander effects, such as enhanced permeability and retention (EPR). A control humanized IgG monoclonal antibody (hIgG1) and an isotype control IgG monoclonal antibody were conjugated with the chelator CHX-A"-DTPA. The immunoconjugate was radiolabeled with either Lutetium-177 ([Lu]Lu) or Indium-111 ([In]In). A biodistribution study in mice carrying LNCaP xenografts, was performed to evaluate the non-specific uptake of [Lu]Lu-hIgG1 in tumors and normal organs. Further, therapy studies of [Lu]Lu and [In]In labeled IgG were performed in BALB/c mice carrying LNCaP xenografts. Tumor tissues of treated xenografts and control were sectioned and immunohistochemically stained for Ki67 and PSA. The highest tumor uptake for the [Lu]Lu-hIgG1 was seen at 72 hours (7.2±2 %IA/g), when comparing the tumor uptake of the fPSA targeting antibody to the non-specific antibody, the non-specific antibody contributes to half of the tumor uptake at 72 h. The liver uptake was 3.1±0.5 %IA/g at 24 h, 2.8±0.5 %IA/g at 72 h and 1.3±0.6 %IA/g at 120 h in LNCaP xenografts, which was approximately three times lower at 24 h and two times lower at 72 h than for the antibody with preserved targeting. Immunohistochemical labeling showed a reduction of PSA expression and a reduction of Ki67 labeled cells in the [In]In treated LNCaP tumors, compared to vehicle and [Lu]Lu treated mice. In conclusion, we found that specific targeting might negatively influence normal organ uptake when targeting secreted antigens. Furthermore, different energy deposition i.e. linear energy transfer of a radionuclide might have diverse effects on receptor expression and cell proliferation in tumors.
我们之前研究了一种靶向游离前列腺特异性抗原（fPSA）的人源化单克隆抗体的生物分布和治疗效果，该抗体用于激素难治性前列腺癌的诊疗。在本研究中，我们使用了一种与之前使用的免疫缀合物具有相同支架但具有随机、非特异性抗原结合区域的抗体，评估了脱靶效应和不同线性能量转移（LET）放射性核素，而不考虑PSA靶向的影响。这使我们能够识别由特异性靶向产生的改变以及与被动旁观者效应相关的改变，如增强的通透性和滞留（EPR）。将对照人源化IgG单克隆抗体（hIgG1）和同型对照IgG单克隆抗体与螯合剂CHX-A”-DTPA偶联。免疫缀合物用镥-177（[Lu]Lu）或铟-111（[In]In）进行放射性标记。在携带LNCaP异种移植瘤的小鼠中进行了生物分布研究，以评估[Lu]Lu-hIgG1在肿瘤和正常器官中的非特异性摄取。此外，在携带LNCaP异种移植瘤的BALB/c小鼠中进行了[Lu]Lu和[In]In标记的IgG的治疗研究。对治疗后的异种移植瘤和对照的肿瘤组织进行切片，并对Ki67和PSA进行免疫组织化学染色。[Lu]Lu-hIgG1在72小时时肿瘤摄取最高（7.2±2 %IA/g），将靶向fPSA的抗体的肿瘤摄取与非特异性抗体相比，非特异性抗体在72小时时占肿瘤摄取的一半。在LNCaP异种移植瘤中，肝脏摄取在24小时时为3.1±0.5 %IA/g，72小时时为2.8±0.5 %IA/g，120小时时为1.3±0.6 %IA/g，与保留靶向的抗体相比，24小时时约低三倍，72小时时约低两倍。免疫组织化学标记显示，与载体和[Lu]Lu处理的小鼠相比，[In]In处理的LNCaP肿瘤中PSA表达降低，Ki67标记的细胞减少。总之，我们发现当靶向分泌抗原时，特异性靶向可能会对正常器官摄取产生负面影响。此外，不同的能量沉积，即放射性核素的线性能量转移，可能会对肿瘤中的受体表达和细胞增殖产生不同的影响。
