89Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted 227Th-conjugate therapy in mice

Linda N Broer; Daan G Knapen; Frans Valentijn Suurs; Ingrid Moen; Danique Giesen; Stijn J H Waaijer; Baard Indrevoll; Christine Ellingsen; Alexander Kristian; Alan S Cuthbertson; Derk-Jan A de Groot; Patricia E Cole; Elisabeth G E de Vries; Urs B Hagemann; Marjolijn N Lub-de Hooge

doi:10.2967/jnumed.121.263079

89Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted 227Th-conjugate therapy in mice

Linda N Broer, Daan G Knapen, Frans Valentijn Suurs, Ingrid Moen, Danique Giesen, Stijn J H Waaijer, Baard Indrevoll, Christine Ellingsen, Alexander Kristian, Alan S Cuthbertson, Derk-Jan A de Groot, Patricia E Cole, Elisabeth G E de Vries, Urs B Hagemann, Marjolijn N Lub-de Hooge^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Rationale: Mesothelin targeted thorium-227 conjugate (227Th-MSLN) is a novel targeted alpha therapy developed to treat mesothelin overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with zirconium-89 (89Zr-MSLN) to evaluate if positron emission tomography (PET) imaging with 89Zr-MSLN matches with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity.

Experimental design: Serial PET imaging with protein doses of 4, 20, or 40 μg 89Zr-MSLN and 89Zr-control was performed up to 168 h post tracer injection (pi) in high (HT29-MSLN) and low (BxPc3) mesothelin expressing human tumor-bearing nude mice. 89Zr-MSLN and 227Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time-points in HT29-MSLN and in medium mesothelin expressing (OVCAR-3) tumor-bearing mice. 89Zr-MSLN PET imaging was performed before 227Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice.

Results: 89Zr-MSLN PET imaging showed mean standardized uptake value (SUVmean) in HT29-MSLN tumors of 2.2 ± 0.5. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram (%ID/g) at 168 h. 89Zr-MSLN tumor uptake was higher than uptake of 89Zr-control (P = 0.0043). 89Zr-MSLN and 227Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. SUVmean was 1.8-fold higher in HT29-MSLN than in BxPc3 tumors, matching with stronger 227Th-MSLN antitumor activity.

Conclusion: 89Zr-MSLN PET imaging reflected mesothelin expression and matched with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Our data support the clinical exploration of 89Zr-MSLN PET imaging together with 227Th-MSLN therapy, both using the same antibody-chelator conjugate.

Original language	English
Pages (from-to)	1715-1721
Number of pages	7
Journal	The Journal of Nuclear Medicine
Volume	63
Issue number	11
Early online date	14-Apr-2022
DOIs	https://doi.org/10.2967/jnumed.121.263079
Publication status	Published - 1-Nov-2022

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10.2967/jnumed.121.263079

89Zr-3,2-HOPO-Mesothelin Antibody PET Imaging Reflects Tumor Uptake of Mesothelin-Targeted 227Th-Conjugate Therapy in MiceFinal publisher's version, 1.41 MBLicence: Taverne

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Broer, L. N., Knapen, D. G., Suurs, F. V., Moen, I., Giesen, D., Waaijer, S. J. H., Indrevoll, B., Ellingsen, C., Kristian, A., Cuthbertson, A. S., de Groot, D.-J. A., Cole, P. E., de Vries, E. G. E., Hagemann, U. B., & Lub-de Hooge, M. N. (2022). 89Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted 227Th-conjugate therapy in mice. The Journal of Nuclear Medicine, 63(11), 1715-1721. https://doi.org/10.2967/jnumed.121.263079

@article{597ac159a4354d98b51c8c2126ed6f24,

title = "89Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted 227Th-conjugate therapy in mice",

abstract = "Rationale: Mesothelin targeted thorium-227 conjugate (227Th-MSLN) is a novel targeted alpha therapy developed to treat mesothelin overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with zirconium-89 (89Zr-MSLN) to evaluate if positron emission tomography (PET) imaging with 89Zr-MSLN matches with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity.Experimental design: Serial PET imaging with protein doses of 4, 20, or 40 μg 89Zr-MSLN and 89Zr-control was performed up to 168 h post tracer injection (pi) in high (HT29-MSLN) and low (BxPc3) mesothelin expressing human tumor-bearing nude mice. 89Zr-MSLN and 227Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time-points in HT29-MSLN and in medium mesothelin expressing (OVCAR-3) tumor-bearing mice. 89Zr-MSLN PET imaging was performed before 227Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice.Results: 89Zr-MSLN PET imaging showed mean standardized uptake value (SUVmean) in HT29-MSLN tumors of 2.2 ± 0.5. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram (%ID/g) at 168 h. 89Zr-MSLN tumor uptake was higher than uptake of 89Zr-control (P = 0.0043). 89Zr-MSLN and 227Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. SUVmean was 1.8-fold higher in HT29-MSLN than in BxPc3 tumors, matching with stronger 227Th-MSLN antitumor activity.Conclusion: 89Zr-MSLN PET imaging reflected mesothelin expression and matched with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Our data support the clinical exploration of 89Zr-MSLN PET imaging together with 227Th-MSLN therapy, both using the same antibody-chelator conjugate.",

author = "Broer, {Linda N} and Knapen, {Daan G} and Suurs, {Frans Valentijn} and Ingrid Moen and Danique Giesen and Waaijer, {Stijn J H} and Baard Indrevoll and Christine Ellingsen and Alexander Kristian and Cuthbertson, {Alan S} and {de Groot}, {Derk-Jan A} and Cole, {Patricia E} and {de Vries}, {Elisabeth G E} and Hagemann, {Urs B} and {Lub-de Hooge}, {Marjolijn N}",

note = "Copyright {\textcopyright} 2022 by the Society of Nuclear Medicine and Molecular Imaging, Inc.",

year = "2022",

month = nov,

day = "1",

doi = "10.2967/jnumed.121.263079",

language = "English",

volume = "63",

pages = "1715--1721",

journal = "The Journal of Nuclear Medicine",

issn = "0161-5505",

publisher = "SOC NUCLEAR MEDICINE INC",

number = "11",

}

Broer, LN, Knapen, DG, Suurs, FV, Moen, I, Giesen, D , Waaijer, SJH, Indrevoll, B, Ellingsen, C, Kristian, A, Cuthbertson, AS, de Groot, D-JA, Cole, PE, de Vries, EGE, Hagemann, UB & Lub-de Hooge, MN 2022, '89Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted 227Th-conjugate therapy in mice', The Journal of Nuclear Medicine, vol. 63, no. 11, pp. 1715-1721. https://doi.org/10.2967/jnumed.121.263079

TY - JOUR

T1 - 89Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted 227Th-conjugate therapy in mice

AU - Broer, Linda N

AU - Knapen, Daan G

AU - Suurs, Frans Valentijn

AU - Moen, Ingrid

AU - Giesen, Danique

AU - Waaijer, Stijn J H

AU - Indrevoll, Baard

AU - Ellingsen, Christine

AU - Kristian, Alexander

AU - Cuthbertson, Alan S

AU - de Groot, Derk-Jan A

AU - Cole, Patricia E

AU - de Vries, Elisabeth G E

AU - Hagemann, Urs B

AU - Lub-de Hooge, Marjolijn N

PY - 2022/11/1

Y1 - 2022/11/1

N2 - Rationale: Mesothelin targeted thorium-227 conjugate (227Th-MSLN) is a novel targeted alpha therapy developed to treat mesothelin overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with zirconium-89 (89Zr-MSLN) to evaluate if positron emission tomography (PET) imaging with 89Zr-MSLN matches with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity.Experimental design: Serial PET imaging with protein doses of 4, 20, or 40 μg 89Zr-MSLN and 89Zr-control was performed up to 168 h post tracer injection (pi) in high (HT29-MSLN) and low (BxPc3) mesothelin expressing human tumor-bearing nude mice. 89Zr-MSLN and 227Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time-points in HT29-MSLN and in medium mesothelin expressing (OVCAR-3) tumor-bearing mice. 89Zr-MSLN PET imaging was performed before 227Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice.Results: 89Zr-MSLN PET imaging showed mean standardized uptake value (SUVmean) in HT29-MSLN tumors of 2.2 ± 0.5. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram (%ID/g) at 168 h. 89Zr-MSLN tumor uptake was higher than uptake of 89Zr-control (P = 0.0043). 89Zr-MSLN and 227Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. SUVmean was 1.8-fold higher in HT29-MSLN than in BxPc3 tumors, matching with stronger 227Th-MSLN antitumor activity.Conclusion: 89Zr-MSLN PET imaging reflected mesothelin expression and matched with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Our data support the clinical exploration of 89Zr-MSLN PET imaging together with 227Th-MSLN therapy, both using the same antibody-chelator conjugate.

AB - Rationale: Mesothelin targeted thorium-227 conjugate (227Th-MSLN) is a novel targeted alpha therapy developed to treat mesothelin overexpressing cancers. We radiolabeled the same antibody-chelator conjugate with zirconium-89 (89Zr-MSLN) to evaluate if positron emission tomography (PET) imaging with 89Zr-MSLN matches with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity.Experimental design: Serial PET imaging with protein doses of 4, 20, or 40 μg 89Zr-MSLN and 89Zr-control was performed up to 168 h post tracer injection (pi) in high (HT29-MSLN) and low (BxPc3) mesothelin expressing human tumor-bearing nude mice. 89Zr-MSLN and 227Th-MSLN ex vivo tumor uptake and biodistribution were compared at 6 time-points in HT29-MSLN and in medium mesothelin expressing (OVCAR-3) tumor-bearing mice. 89Zr-MSLN PET imaging was performed before 227Th-MSLN treatment in HT29-MSLN and BxPc3 tumor-bearing mice.Results: 89Zr-MSLN PET imaging showed mean standardized uptake value (SUVmean) in HT29-MSLN tumors of 2.2 ± 0.5. Ex vivo tumor uptake was 10.6% ± 2.4% injected dose per gram (%ID/g) at 168 h. 89Zr-MSLN tumor uptake was higher than uptake of 89Zr-control (P = 0.0043). 89Zr-MSLN and 227Th-MSLN showed comparable tumor uptake and biodistribution in OVCAR-3 and HT29-MSLN tumor-bearing mice. SUVmean was 1.8-fold higher in HT29-MSLN than in BxPc3 tumors, matching with stronger 227Th-MSLN antitumor activity.Conclusion: 89Zr-MSLN PET imaging reflected mesothelin expression and matched with 227Th-MSLN tumor uptake, biodistribution, and antitumor activity. Our data support the clinical exploration of 89Zr-MSLN PET imaging together with 227Th-MSLN therapy, both using the same antibody-chelator conjugate.

U2 - 10.2967/jnumed.121.263079

DO - 10.2967/jnumed.121.263079

M3 - Article

C2 - 35422447

SN - 0161-5505

VL - 63

SP - 1715

EP - 1721

JO - The Journal of Nuclear Medicine

JF - The Journal of Nuclear Medicine

IS - 11

ER -

89Zr-3,2-HOPO-mesothelin antibody PET imaging reflects tumor uptake of mesothelin targeted 227Th-conjugate therapy in mice

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