Radiotheranostic targeting of fPSA
Venue: Nature Reviews Urology
Year: 2021

0123456789(  Research have described the development of a novel theranostic approach using a humanized antibody hu5A10 that can be used for downstream targeting of the androgen receptor (AR) in PSAexpressing tissues and has potential for translation into clinical use in men with prostate cancer. A multicentre group led by David Ulmert at the University of California, Los Angeles, performed preclinical studies in both mice and nonhuman primates (NHP) Although ARtargeted therapies are effective in many men with prostate cancer, the development of resistance and escape mechanisms means that these strategies can often, ultimately, fail. PSMAtargeted radiotheranostics are available, but using the alternative target of free PSA (fPSA; also known as kallikrein 3 (KLK3) is also valuable. "Over the past few decades, the classic kallikreins (KLK1 3) have been extensively studied," comments Ulmert. "Differences in tissue expressions highlight the advantages of targeting PSA and human kallikrein 2 (hK2, which shares 80% amino acid sequence identity with PSA) While PSMA is found in several nonprostatic organs, both PSA and hK2 are very specific to ARdriven healthy and malignant prostate tissues." Thus, Ulmert's team investigated the potential of using a humanized monoclonal antibody (mAb) hu5A10, to target the AR pathway via fPSA in a number of preclinical models. The technology used in the studies exploits the high affinity and specificity of the antibody to bind to catalytic clefts in fPSA, which are not exposed in complexed PSA, and the specific mechanism of the neonatal Fc receptor, which causes the antigenbound antibodies to be rerouted and internalized in target cells, where accumulation of the mAbs in diseased tissue can be imaged and, therefore, used diagnostically or therapeutically. First, the team demonstrated specificity of the labelled hu5A10 using LNCaPAR prostate cell line tumour xenografts in mice. These studies showed that [89Zr]hu5A10 uptake in the tumours increased over time, which was not seen in healthy tissues. The biodistribution of the mAb correlated with the expression of KLK3, whereby high KLK3expressing tumours showed an increased mean uptake of [89Zr] hu5A10, with an expression pattern in the prostatic lobes that reflected KLK3 expression in prostate. After determining that hu5A10 can bind to cynomolgus macaque PSA, studies in NHPs were used to determine the in vivo biodistribution and for imaging. [89Zr]hu5A10 (0.2 mg/kg; 115 11 MBq) was administered to three adult, male cynomolgus macaques and PET CT imaging was performed over 2 weeks, during which no adverse events or physiological responses were observed. The prostate gland was clearly visualized using [89Zr]hu5A10 PET CT over the observation period with SUVmean reaching 5.9 2.3 at 1 h after the injection, which then decreased to SUVmean 4.5 1.4 (at 2 3 days) 2.9 1.2 (at 5 6 days) and 2.0 0.6 (at 9 13 days) Significant uptake was also seen in the epididymis, with lower uptake in the testis and minimal uptake in the seminal vesicles. Little offtarget radioactivity was seen (SUVmean <1 in bladder and intestine) but the majority that did occur was in the liver and was not excreted. This ability to visualize offtarget effects is beneficial, as Ulmert explains: "The concept and advantages of radiotheranostics are that the PET images show the exact location and dose of the cytotoxic radionuclides that will be delivered. In other words, it is easy to foresee potential organ toxicities by studying offtarget, nonprostatetissue uptake identified on imaging." These data illustrate the potential of targeting prostate kallikreins theranostically. In fact, this approach has some advantages over the use of PSMA, which is already well established. According to Ulmert: "An important feature is AR regulation; whereas a positive correlation between AR and PSMA exists during early stages of prostate cancer, the opposite is evident later down the road that is, activation of AR results in downregulation of PSMA. By contrast, prostate kallikrein expression consistently follows AR activity in a positive manner. This feature is a clear advantage for PSA over PSMA when applying the targets for imaging and treatment."