PSA-targeted alpha-, beta-, and positron-emitting immunotheranostics in murine prostate cancer models and nonhuman primates Journal Article


Authors: Veach, D. R.; Storey, C. M.; Lückerath, K.; Braun, K.; von Bodman, C.; Lamminmäki, U.; Kalidindi, T.; Strand, S. E.; Strand, J.; Altai, M.; Damoiseaux, R.; Zanzonico, P.; Benabdallah, N.; Pankov, D.; Scher, H. I.; Scardino, P.; Larson, S. M.; Lilja, H.; McDevitt, M. R.; Thorek, D. L. J.; Ulmert, D.
Article Title: 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 Zr-89- or treated with Y-90- or Ac-225-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [Ac-225]hu5A10 and [Y-99]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [Zr-89]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 [Y-90]/[Ac-225]hu5A10 effectively reduced tumor burden and prolonged survival (P <= 0.0054). Effects of [Y-98]hu5A10 were more immediate than [Ac-225]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [Ac-225]hu5A10 and 1 of 9 mice [Y-90]hu5A10. Pharmacokinetics of [Zr-89]hu5A10 were consistent between NHPs and comparable with those in mice. [Zr-89]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.
Journal Title: Clinical Cancer Research
Volume: 27
Issue: 7
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2021-04-01
Start Page: 2050
End Page: 2060
Language: English
ACCESSION: WOS:000636977600026
DOI: 10.1158/1078-0432.Ccr-20-3614
PROVIDER: wos
PUBMED: 33441295
Notes: Article -- Source: Wos
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MSK Authors
  1. Peter T Scardino
    644 Scardino
  2. Michael R Mcdevitt
    131 Mcdevitt
  3. Darren Veach
    75 Veach
  4. Hans Gosta Lilja
    312 Lilja
  5. Pat B Zanzonico
    295 Zanzonico
  6. Steven M Larson
    902 Larson
  7. Dmitry D. Pankov
    21 Pankov
  8. Howard Scher
    1033 Scher