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

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

doi:10.1158/1078-0432.CCR-20-3614

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

Clin Cancer Res. 2021 Apr 1;27(7):2050-2060. doi: 10.1158/1078-0432.CCR-20-3614. Epub 2021 Jan 13.

Authors

Darren R Veach^{1

2}, Claire M Storey³, Katharina Lückerath^{3

4

5

6}, Katharina Braun⁷, Christian von Bodman⁸, Urpo Lamminmäki⁹, Teja Kalidindi¹, Sven-Erik Strand¹⁰, Joanna Strand¹⁰, Mohamed Altai¹⁰, Robert Damoiseaux³, Pat Zanzonico¹¹, Nadia Benabdallah¹², Dmitry Pankov¹³, Howard I Scher^{14

15}, Peter Scardino^{15

16}, Steven M Larson^{1

2}, Hans Lilja^{14

16

17

18}, Michael R McDevitt^{1

2}, Daniel L J Thorek^{12

19}, David Ulmert^{20

4

5

6

21}

Affiliations

¹ Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
² Department of Radiology, Weill Cornell Medical College, New York, New York.
³ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California.
⁴ Ahmanson Translational Imaging Division, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
⁵ Department of Urology, David Geffen School of Medicine, Institute of Urologic Oncology, University of California, Los Angeles, Los Angeles, California.
⁶ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
⁷ Department of Urology, Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany.
⁸ Uroviva - Specialized Clinic for Urology, Bülach, Switzerland.
⁹ Department of Biochemistry, University of Turku, Turku, Finland.
¹⁰ Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden.
¹¹ Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York.
¹² Department of Radiology, Washington University School of Medicine, St. Louis, Missouri.
¹³ Immunology Program, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
¹⁴ Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
¹⁵ Department of Medicine, Weill Cornell Medical College, New York, New York.
¹⁶ Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
¹⁷ Department of Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
¹⁸ Department of Translational Medicine, Lund University, Malmö, Sweden.
¹⁹ Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, Missouri.
²⁰ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California. hdsulmert@gmail.com.
²¹ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California.

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 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 PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alpha Particles / therapeutic use*
Animals
Beta Particles / therapeutic use*
Disease Models, Animal
Electrons / therapeutic use*
Linear Energy Transfer
Macaca fascicularis
Male
Mice
Mice, Inbred BALB C
Positron-Emission Tomography
Prostate-Specific Antigen / immunology*
Prostate-Specific Antigen / metabolism
Prostatic Neoplasms / radiotherapy*
Radioimmunotherapy / methods*
Receptors, Androgen / physiology
Tissue Distribution

Substances

Receptors, Androgen
Prostate-Specific Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding