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.
Funding Information:
K. Lu€ckerath reports personal fees from Sofie Biosciences outside the submitted work. U. Lamminm€aki reports a patent for WO2017060247A1 pending. S.-E. Strand reports grants from Swedish Cancer Foundation and Swedish Research Council during the conduct of the study; in addition, S.-E. Strand had a patent for HUMANIZED ANTI PSA (5A10) ANTIBODIES issued to PCT/EP2016/073684. R. Damoiseaux reports a patent for Antibodies pending. H.I. Scher reports personal fees from Asterias Biotherapeutics, Bayer, Pfizer, Inc, Sun Pharmaceuticals Industries, Inc., WCG; nonfinancial support from Amgen, ESSA Pharma Inc, Janssen Research & Development, LLC, Janssen Biotech, Inc, and Menarini Silicon Biosystems; and grants from Epic Sciences, Illumina, Inc., Janssen, Menarini Silicon Biosystems, and Thermo Fisher Scientific outside the submitted work; in addition, H.I. Scher has a patent 10,736,972 issued and licensed to Elucida Oncology, a patent for 16/463,865 pending and licensed to Elucida Oncology, and a patent for 16/769,501 pending and licensed to Elucida Oncology. P. Scardino reports other from OPKO Biotech, Advantagene, and INsightec outside the submitted work. S.M. Larson reports grants from NIH during the conduct of the study, and grants from YMABS Therapeutics Inc and royalties from Elucida, SAMOs, and YMABS Therapeutic Inc outside the submitted work; in addition, S.M. Larson has several patents in the field of Radioimmunotherapy and Drug delivery pending, issued, licensed, and with royalties paid from YMABS Therapeutic; a patent for Nanoparticles issued, licensed, and with royalties paid from Elucida Inc; and a patent for radiotracer drugs from SAMOS; and reports consultation regarding drug products with Progenics, Janssen, and Exini (Lantheus) during the conduct of this work and preparation of article. H. Lilja is named on patents for intact PSA assays and a statistical method to detect prostate cancer (4KScore test) that has been commercialized by OPKO Health; receives royalties from sales of the test and has stock in OPKO Health; was a consultant to Diaprost AB and has stock options and stock in Diaprost AB; and received a speakers honorarium from Janssen R&D LLC. D.L.J. Thorek reports grants from NIH NCI (R0128335, R0128238, R0128539) during the conduct of the study and is scientific advisor for and has equity in Diaprost AB. D. Ulmert reports grants from Prostate Cancer Foundation and Department of Defense during the conduct of the study; in addition, D. Ulmert has a patent for EP2771688A4 issued to Diaprost, a patent for US20190381200A1 pending, and a patent for US20180326102A1 pending, and is a board member for Diaprost AB, the Swedish company that holds and has licensed patents on the humanized version of the antibody (hu5A10) utilized in the study. No disclosures were reported by the other authors.
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
VL - 27
SP - 2050
EP - 2060
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 7
ER -