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Supplementary Figure S1 from PSA-Targeted Alpha-, Beta-, and Positron-Emitting Immunotheranostics in Murine Prostate Cancer Models and Nonhuman Primates

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posted on 2023-03-31, 22:45 authored by Darren R. Veach, Claire M. Storey, Katharina Lückerath, Katharina Braun, Christian von Bodman, Urpo Lamminmäki, Teja Kalidindi, Sven-Erik Strand, Joanna Strand, Mohamed Altai, Robert Damoiseaux, Pat Zanzonico, Nadia Benabdallah, Dmitry Pankov, Howard I. Scher, Peter Scardino, Steven M. Larson, Hans Lilja, Michael R. McDevitt, Daniel L.J. Thorek, David Ulmert

Supplementary Figure S1. Ex-vivo biodistribution of [89Zr]hu5A10.

Funding

NIH

Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center

Radiochemistry & Molecular Imaging Probe Core

NCI

MSKCC

SPORE in Prostate Cancer

National Cancer Institute

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Swedish Cancer Society

Swedish Research Council

DoD

Prostate Cancer

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ARTICLE ABSTRACT

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). 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. 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. 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.

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