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Updated: Nov 21, 2025
Pre-clinical Orthotopic Murine Model of Human Prostate Cancer
Published on: August 29, 2016
PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman
Darren R Veach1,2, Claire M Storey3, Katharina Lückerath3,4,5,6
1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA (KLK3).
Experimental Design:
LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3_Hi-Myc transgenic mice were imaged with 89Zr- or treated with 90Y- or 225Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [225Ac]hu5A10 and [90Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89Zr]hu5A10 in nonhuman primates (NHP) were determined using PET.
Results:
Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90Y]/[225Ac]hu5A10 effectively reduced tumor burden and prolonged survival (P ≤ 0.0054). Effects of [90Y]hu5A10 were more immediate than [225Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [225Ac]hu5A10 and 1 of 9 mice [90Y]hu5A10. Pharmacokinetics of [89Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [89Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period.
Conclusions:
We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.
Insights
This study shows hu5A10, a novel antibody targeting prostate-specific antigen (PSA), effectively treats prostate cancer in preclinical models. Radiolabeled hu5A10 demonstrates theranostic potential for advanced prostate cancer therapy.
Area of Science:
- Oncology
- Radiopharmaceutical Therapy
- Immunotherapy
Background:
- Androgen receptor (AR) signaling inhibitors are standard prostate cancer treatments.
- Therapeutic resistance to AR inhibitors is common due to AR functionality restoration.
- Novel therapeutic strategies targeting AR are critically needed.
Purpose of the Study:
- To investigate the theranostic potential of hu5A10, a humanized monoclonal antibody targeting free prostate-specific antigen (PSA, KLK3).
- To evaluate the efficacy and biodistribution of radiolabeled hu5A10 in preclinical prostate cancer models.
Main Methods:
- Radiolabeling hu5A10 with isotopes (89Zr, 90Y, 225Ac) for imaging and therapy.
- In vivo studies using LNCaP-AR xenografts and KLK3_Hi-Myc transgenic mice.
- Assessment of biodistribution, tumor uptake, therapeutic efficacy, and pharmacokinetics in mice and nonhuman primates (NHPs).
Main Results:
- Radiolabeled hu5A10 showed specific tumor uptake correlating with PSA expression.
- Treatment with 90Y- or 225Ac-labeled hu5A10 significantly reduced tumor burden and prolonged survival.
- Complete responses were observed in a subset of animals treated with 225Ac-hu5A10.
- 89Zr-hu5A10 PET visualized prostate in NHPs, consistent with mouse pharmacokinetics.
Conclusions:
- Hu5A10 establishes a new theranostic agent for highly specific and effective targeting of AR in PSA-expressing tissues.
- Preclinical data support the clinical translation of radiolabeled hu5A10 for prostate cancer treatment.
- This approach offers a promising strategy for overcoming therapeutic resistance in prostate cancer.
