TY - JOUR
T1 - PSA-Targeted Alpha-, Beta-, and Positron-emitting immunotheranostics in murine prostate cancer models and nonhuman primates
AU - Veach, Darren R.
AU - Storey, Claire M.
AU - Lückerath, Katharina
AU - Braun, Katharina
AU - Von Bodman, Christian
AU - Lamminmäki, Urpo
AU - Kalidindi, Teja
AU - Strand, Sven Erik
AU - Strand, Joanna
AU - Altai, Mohamed
AU - Damoiseaux, Robert
AU - Zanzonico, Pat
AU - Benabdallah, Nadia
AU - Pankov, Dmitry
AU - Scher, Howard I.
AU - Scardino, Peter
AU - Larson, Steven M.
AU - Lilja, Hans
AU - McDevitt, Michael R.
AU - Thorek, Daniel L.J.
AU - Ulmert, David
N1 - Funding Information:
This study was supported in part by the Imaging and Radiation Sciences Program, U.S. NIH grant P30 CA008748 (MSKCC Support Grant). The MSKCC Small-Animal Imaging Core Facility is supported in part by NIH grants P30 CA008748-48, S10 RR020892-01, S10 RR028889-01, and the Geoffrey Beene Cancer Research Center.
Funding Information:
This study was supported in part by the Imaging and Radiation Sciences Program, U.S. NIHgrant P30 CA008748 (MSKCC Support Grant). The MSKCC Small-Animal Imaging Core Facility is supported in part by NIH grants P30 CA008748-48, S10 RR020892-01, S10 RR028889-01, and the Geoffrey Beene Cancer Research Center. We also acknowledge William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center, and the Radiochemistry & Molecular Imaging Probe Core (P50-CA086438), all of MSKCC. M.R. McDevitt: NIH R01CA166078, R01CA55349, P30CA008748, P01CA33049, F31CA167863, the MSKCC for Molecular Imaging and Nanotechnology. D.L.J. Thorek: NCI R01CA201035, R01CA240711, and R01CA229893. H. Lilja, H.I. Scher: NIH/NCI CCSG to MSKCC (P30 CA008748). H.I. Scher: SPORE in Prostate Cancer (P50 CA092629). H. Lilja: Sidney Kimmel Center for Prostate and Urologic Cancers. David H. Koch Prostate Cancer Foundation Award, Swedish Cancer Society (CAN2017/559), Swedish Research Council (VR-MH2016-02974), General Hospital in Malmö Foundation for Combating Cancer. D.L.J. Thorek: NCI R01CA201035, R01CA240711, R01CA229893. D. Ulmert, M.R. McDevitt: DoD W81XWH-18-1- 0223. D. Ulmert: UCLA SPORE in Prostate Cancer (P50 CA092131), JCCC Cancer support grant from NIH P30 CA016042 (PI: Teitell), Knut and Alice Wallenberg Foundation, Bertha Kamprad Foundation, David H. Koch Prostate Cancer Foundation Young Investigator Award. S.M. Larson: Ludwig Center for Cancer Immunotherapy (MSKCC), NCI P50-CA86438. S.-E. Strand: Swedish Cancer Society, Swedish National Health Foundation, Swedish Research Council.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - 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 PSAexpressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.
AB - 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 PSAexpressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.
UR - http://www.scopus.com/inward/record.url?scp=85101020937&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-3614
DO - 10.1158/1078-0432.CCR-20-3614
M3 - Article
C2 - 33441295
AN - SCOPUS:85101020937
SN - 1078-0432
VL - 27
SP - 2050
EP - 2060
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -