Dataset Information

PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates.

ABSTRACT:

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.

SUBMITTER: Veach DR

PROVIDER: S-EPMC8278668 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates.

Veach Darren R DR Storey Claire M CM Lückerath Katharina K Braun Katharina K von Bodman Christian C Lamminmäki Urpo U Kalidindi Teja T Strand Sven-Erik SE Strand Joanna J Altai Mohamed M Damoiseaux Robert R Zanzonico Pat P Benabdallah Nadia N Pankov Dmitry D Scher Howard I HI Scardino Peter P Larson Steven M SM Lilja Hans H McDevitt Michael R MR Thorek Daniel L J DLJ Ulmert David D

Clinical cancer research : an official journal of the American Association for Cancer Research 20210113 7

<h4>Purpose</h4>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 (<i>KLK3</i>).<h4>Experimental design</h4>LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and <i>KLK3</i>_Hi-<i>Myc</i> transge ...[more]

PMID: 33441295

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Dataset Information

PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates.

Purpose

Experimental design

Results

Conclusions

Publications

PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates.

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