Abstract
Simple SummaryThe present study demonstrates that a radiolabeling strategy can positively modify hu5A10′s capacity to bind PSA and complex with the FcRn receptor, which results in a more homogenous activity distribution in tumors and enhanced therapy efficacy. These new innovative radiochemistry ideas could potentially decrease relapse of tumors in patients treated with internalizing antibodies.Background: The humanized monoclonal antibody (mAb) hu5A10 specifically targets and internalizes prostate cancer cells by binding to prostate specific antigen (PSA). Preclinical evaluations have shown that hu5A10 is an excellent vehicle for prostate cancer (PCa) radiotheranostics. We studied the impact of different chelates and conjugation ratios on hu5A10′s target affinity, neonatal fc-receptor interaction on in vivo targeting efficacy, and possible enhanced therapeutic efficacy. Methods: In our experiment, humanized 5A10 (hu5A10) was conjugated with DOTA or DTPA at a molar ratio of 3:1, 6:1, and 12:1. Surface plasmon resonance (SPR) was used to study antigen and FcRn binding to the antibody conjugates. [111In]hu5A10 radio-immunoconjugates were administered intravenously into BALB/c mice carrying subcutaneous LNCaP xenografts. Serial Single-photon emission computed tomography (SPECT) images were obtained during the first week. Tumors were harvested and radionuclide distribution was analyzed by autoradiography along with microanatomy and immunohistochemistry. Results: As seen by SPR, the binding to PSA was clearly affected by the chelate-to-antibody ratio. Similarly, FcRn (neonatal fc-receptor) interacted less with antibodies conjugated at high ratios of chelator, which was more pronounced for DOTA conjugates. The autoradiography data indicated a higher distribution of radioactivity to the rim of the tumor for lower ratios and a more homogenous distribution at higher ratios. Mice injected with ratio 3:1 111In-DOTA-hu5A10 showed no significant difference in tumor volume when compared to mice given vehicle over a time period of 3 weeks. Mice given a similar injection of ratio 6:1 111In-DOTA-hu5A10 or 6:1 111In-DTPA-hu5A10 or 12:1 111In-DTPA-hu5A10 showed significant tumor growth retardation. Conclusions: The present study demonstrated that the radiolabeling strategy could positively modify the hu5A10′s capacity to bind PSA and complex with the FcRn-receptor, which resulted in more homogenous activity distribution in tumors and enhanced therapy efficacy.
Highlights
Prostate cancer (PCa) is the most common cancer in men in the Western world [1].One of every 8–10 patients diagnosed with prostate cancer (PCa) will die from this disease
We have evaluated the influence of an increasing number of the p-SCN-CHX-A”DTPA or p-SCN-Bn-DOTA chelators per Humanized 5A10 (hu5A10) monoclonal antibody (mAb) with regards to free PSA (fPSA) binding, fc-receptor-driven process (FcRn) interaction, tumor penetration, and blood retention
Data are presented as changes in relative tumor size ratio (log(RTS)), as well as weight changes during therapy, for the different therapy groups It can be clearly seen that the therapy efficacy was highly dependent of the choice of chelator and chelate-to-antibody molar ratio
Summary
Prostate cancer (PCa) is the most common cancer in men in the Western world [1].One of every 8–10 patients diagnosed with PCa will die from this disease. There is currently no curative treatment for patients with metastatic castration-resistant prostate cancer (mCRPC), despite an expanding arsenal of targeted agents to treat and monitor the disease. Treatments of prostate cancer are currently focusing on targets downstream of the androgen receptor (AR) pathway such as prostate-specific membrane antigen (PSMA) [3]. One promising strategy to manage metastatic PCa is targeted radionuclide therapy [4]. Both lutetium177-labeled PSMA-targeted antibodies (J591) and small molecules have shown promising anti-tumor effects, albeit often transitory and with decreasing therapeutic efficacy upon re-dosing. It is known that AR signaling results in down-regulation of FOLH1, the gene coding for PSMA (folate hydrolase 1, FOLH1), and subsequently a lower expression of PSMA This has presented a challenge, as it impacts the diagnostic readout for PSMA ligand positron emission tomography (PET). We studied the impact of different chelates and conjugation ratios on hu5A100 s target affinity, neonatal fc-receptor interaction on in vivo targeting efficacy, and possible enhanced therapeutic efficacy
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