An antibody-radionuclide conjugate targets fibroblast activation protein for cancer therapy
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature..
PURPOSE: Fibroblast activation protein is one of the most attractive targets for tumor diagnosis and therapy. There have been many successful clinical translations with small molecules and peptides, yet only a few anti-FAP antibody diagnostic or therapeutic agents have been reported. Antibodies often feature good tumor selectivity and long tumor retention, which may be a better-match with therapeutic radionuclides (e.g.,177Lu, 225Ac) for cancer therapy. Here we report a 177Lu-labeled anti-FAP antibody, PKU525, as a therapeutic radiopharmaceutical for FAP-targeted radiotherapy.
METHODS: The anti-FAP antibody is produced as a derivative of sibrotuzumab. The pharmacokinetics and blocking study are performed with 89Zr-labeled antibody by PET imaging. The conjugation strategies have been screened and tested with SPECT imaging through 177Lu-labeling. The biodistribution and radiotherapy studies are performed on 177Lu-labeled anti-FAP antibody in NU/NU mice-bearing HT-1080-FAP tumors.
RESULTS: A multiple time-point PET imaging study shows that the tumor accumulation of [89Zr]Zr-DFO-PKU525 is intense, selective, and relatively rapid. The time activity curve indicates that the tumor uptake continually increases until reaches the highest uptake (SUVmax = 18.4 ± 2.3, n = 4) at 192 h, then gradually declines. Radioactivity rapidly cleared from the blood, liver, and other major organs, resulting in high tumor-to-background ratios. An in vivo blocking experiment suggests that [89Zr]Zr-DFO-PKU525 is FAP-specific and the uptake in FAP-negative tumors is almost negligible. Ex vivo biodistribution study shows that the tumor uptake of [177Lu]Lu-DOTA-NCS-PKU525 is 23.04 ± 5.11% ID/g, 33.2 ± 6.36% ID/g, 19.87 ± 6.84% ID/g and 19.02 ± 5.90% ID/g at 24 h, 96 h, 168 h, and 240 h after injection (n = 5), which is corroborated with the PET imaging. In therapeutic assays, multiple doses of [177Lu]Lu-DOTA-NCS-PKU525 have been tested in tumor-bearing mice, and the data suggests that 3.7 MBq may be sufficient to completely suppress the tumor growth in mice without showing observable side effects.
CONCLUSION: A FAP-targeted antibody-radionuclide conjugate was developed and evaluated in vitro and in vivo. Its tumor accumulation is rapid and high with a clean background. It remarkably suppresses the tumors in mice while the side effect is almost negligible, showing that it is promising for further clinical translational studies.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:50 |
|---|---|
| Enthalten in: |
European journal of nuclear medicine and molecular imaging - 50(2023), 11 vom: 15. Sept., Seite 3214-3224 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Xu, Mengxin [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Antibody |
|---|
| Anmerkungen: |
Date Completed 23.10.2023 Date Revised 01.01.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s00259-023-06300-6 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM358201365 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM358201365 | ||
| 003 | DE-627 | ||
| 005 | 20240108140716.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s00259-023-06300-6 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1246.xml |
| 035 | |a (DE-627)NLM358201365 | ||
| 035 | |a (NLM)37318538 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Xu, Mengxin |e verfasserin |4 aut | |
| 245 | 1 | 3 | |a An antibody-radionuclide conjugate targets fibroblast activation protein for cancer therapy |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 23.10.2023 | ||
| 500 | |a Date Revised 01.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. | ||
| 520 | |a PURPOSE: Fibroblast activation protein is one of the most attractive targets for tumor diagnosis and therapy. There have been many successful clinical translations with small molecules and peptides, yet only a few anti-FAP antibody diagnostic or therapeutic agents have been reported. Antibodies often feature good tumor selectivity and long tumor retention, which may be a better-match with therapeutic radionuclides (e.g.,177Lu, 225Ac) for cancer therapy. Here we report a 177Lu-labeled anti-FAP antibody, PKU525, as a therapeutic radiopharmaceutical for FAP-targeted radiotherapy | ||
| 520 | |a METHODS: The anti-FAP antibody is produced as a derivative of sibrotuzumab. The pharmacokinetics and blocking study are performed with 89Zr-labeled antibody by PET imaging. The conjugation strategies have been screened and tested with SPECT imaging through 177Lu-labeling. The biodistribution and radiotherapy studies are performed on 177Lu-labeled anti-FAP antibody in NU/NU mice-bearing HT-1080-FAP tumors | ||
| 520 | |a RESULTS: A multiple time-point PET imaging study shows that the tumor accumulation of [89Zr]Zr-DFO-PKU525 is intense, selective, and relatively rapid. The time activity curve indicates that the tumor uptake continually increases until reaches the highest uptake (SUVmax = 18.4 ± 2.3, n = 4) at 192 h, then gradually declines. Radioactivity rapidly cleared from the blood, liver, and other major organs, resulting in high tumor-to-background ratios. An in vivo blocking experiment suggests that [89Zr]Zr-DFO-PKU525 is FAP-specific and the uptake in FAP-negative tumors is almost negligible. Ex vivo biodistribution study shows that the tumor uptake of [177Lu]Lu-DOTA-NCS-PKU525 is 23.04 ± 5.11% ID/g, 33.2 ± 6.36% ID/g, 19.87 ± 6.84% ID/g and 19.02 ± 5.90% ID/g at 24 h, 96 h, 168 h, and 240 h after injection (n = 5), which is corroborated with the PET imaging. In therapeutic assays, multiple doses of [177Lu]Lu-DOTA-NCS-PKU525 have been tested in tumor-bearing mice, and the data suggests that 3.7 MBq may be sufficient to completely suppress the tumor growth in mice without showing observable side effects | ||
| 520 | |a CONCLUSION: A FAP-targeted antibody-radionuclide conjugate was developed and evaluated in vitro and in vivo. Its tumor accumulation is rapid and high with a clean background. It remarkably suppresses the tumors in mice while the side effect is almost negligible, showing that it is promising for further clinical translational studies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Antibody | |
| 650 | 4 | |a Fibroblast activation protein | |
| 650 | 4 | |a Targeted radionuclide therapy | |
| 650 | 7 | |a Radioisotopes |2 NLM | |
| 650 | 7 | |a Radiopharmaceuticals |2 NLM | |
| 650 | 7 | |a Immunoconjugates |2 NLM | |
| 700 | 1 | |a Chen, Junyi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Pu |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Song, Hanbo |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhibo |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t European journal of nuclear medicine and molecular imaging |d 2002 |g 50(2023), 11 vom: 15. Sept., Seite 3214-3224 |w (DE-627)NLM116957360 |x 1619-7089 |7 nnns |
| 773 | 1 | 8 | |g volume:50 |g year:2023 |g number:11 |g day:15 |g month:09 |g pages:3214-3224 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s00259-023-06300-6 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 50 |j 2023 |e 11 |b 15 |c 09 |h 3214-3224 | ||