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

Authors :
Veach DR
Storey CM
Lückerath K
Braun K
von Bodman C
Lamminmäki U
Kalidindi T
Strand SE
Strand J
Altai M
Damoiseaux R
Zanzonico P
Benabdallah N
Pankov D
Scher HI
Scardino P
Larson SM
Lilja H
McDevitt MR
Thorek DLJ
Ulmert D
Source :
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Apr 01; Vol. 27 (7), pp. 2050-2060. Date of Electronic Publication: 2021 Jan 13.
Publication Year :
2021

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 ).<br />Experimental Design: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3 _Hi- Myc transgenic mice were imaged with <superscript>89</superscript> Zr- or treated with <superscript>90</superscript> Y- or <superscript>225</superscript> Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [ <superscript>225</superscript> Ac]hu5A10 and [ <superscript>90</superscript> Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [ <superscript>89</superscript> Zr]hu5A10 in nonhuman primates (NHP) were determined using PET.<br />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 [ <superscript>90</superscript> Y]/[ <superscript>225</superscript> Ac]hu5A10 effectively reduced tumor burden and prolonged survival ( P ≤ 0.0054). Effects of [ <superscript>90</superscript> Y]hu5A10 were more immediate than [ <superscript>225</superscript> Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [ <superscript>225</superscript> Ac]hu5A10 and 1 of 9 mice [ <superscript>90</superscript> Y]hu5A10. Pharmacokinetics of [ <superscript>89</superscript> Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [ <superscript>89</superscript> Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period.<br />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.<br /> (©2021 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1557-3265
Volume :
27
Issue :
7
Database :
MEDLINE
Journal :
Clinical cancer research : an official journal of the American Association for Cancer Research
Publication Type :
Academic Journal
Accession number :
33441295
Full Text :
https://doi.org/10.1158/1078-0432.CCR-20-3614