(90) Y/(177) Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation
Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG1 mAb that binds to the epidermal growth factor receptor with high aff...
Saved in:
Published in | Journal of labelled compounds & radiopharmaceuticals Vol. 59; no. 9; pp. 354 - 363 |
---|---|
Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
England
01.07.2016
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Abstract | Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG1 mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of (90) Y-labelled Cetuximab and (177) Lu-labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N-[(R)-2-amino-3-(paraisothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N″,N″-pentaacetic acid (CHX-A″-DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for (90) Y-CHX-A″-DTPA-Cetuximab and 1.14 ± 0.15 GBq/mg for (177) Lu-CHX-A″-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both (90) Y-CHX-A″-DTPA-Cetuximab and (177) Lu-CHX-A″-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (~16%ID/g) with good tumour-to-background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of (90) Y-CHX-A″-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation. |
---|---|
AbstractList | Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG1 mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of (90) Y-labelled Cetuximab and (177) Lu-labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N-[(R)-2-amino-3-(paraisothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N″,N″-pentaacetic acid (CHX-A″-DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for (90) Y-CHX-A″-DTPA-Cetuximab and 1.14 ± 0.15 GBq/mg for (177) Lu-CHX-A″-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both (90) Y-CHX-A″-DTPA-Cetuximab and (177) Lu-CHX-A″-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (~16%ID/g) with good tumour-to-background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of (90) Y-CHX-A″-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation. Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG1 mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of (90) Y-labelled Cetuximab and (177) Lu-labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N-[(R)-2-amino-3-(paraisothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N″,N″-pentaacetic acid (CHX-A″-DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for (90) Y-CHX-A″-DTPA-Cetuximab and 1.14 ± 0.15 GBq/mg for (177) Lu-CHX-A″-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both (90) Y-CHX-A″-DTPA-Cetuximab and (177) Lu-CHX-A″-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (~16%ID/g) with good tumour-to-background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of (90) Y-CHX-A″-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation. |
Author | Nair, K V Vimalnath Rajeswari, Ardhi Chakraborty, Sudipta Sarma, Haladhar Dev Chakravarty, Rubel Dash, Ashutosh |
Author_xml | – sequence: 1 givenname: Rubel surname: Chakravarty fullname: Chakravarty, Rubel organization: Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India – sequence: 2 givenname: Sudipta surname: Chakraborty fullname: Chakraborty, Sudipta organization: Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India – sequence: 3 givenname: Haladhar Dev surname: Sarma fullname: Sarma, Haladhar Dev organization: Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India – sequence: 4 givenname: K V Vimalnath surname: Nair fullname: Nair, K V Vimalnath organization: Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India – sequence: 5 givenname: Ardhi surname: Rajeswari fullname: Rajeswari, Ardhi organization: Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India – sequence: 6 givenname: Ashutosh surname: Dash fullname: Dash, Ashutosh organization: Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27264196$$D View this record in MEDLINE/PubMed |
BookMark | eNo1kEtLAzEUhYMo9qEL_4Bk2S6mzWsecSfFFxTc6MLVkMmkmpLHOEnA-usNWleHyzkczndn4NR5pwC4wmiFESLrvZHjijJMT8AUI84LTBmbgFkIe4Tyzdg5mJCaVAzzagrsgqMlfFsvcF0v4TYVRnTKGNXDjYrpS1vRQW1tcl56t0_vIqpwA0fRay8_lNUhjgfoh6it_hZRewejh9Jop6UwsPdBwZ0fbTK_5gU42wkT1OVR5-D1_u5l81hsnx-eNrfbYsijYtEQzGQlFGMc8WrXcUFEKVkjucQ1o6LDtCxRRqgrIkjHMlVZypIg3vRSNYLOweKvdxj9Z1IhtnmpzFzCKZ9CixtEWF3n-hy9PkZTZ1XfDmNmHg_t_4voDyCWZu8 |
ContentType | Journal Article |
Copyright | Copyright © 2016 John Wiley & Sons, Ltd. |
Copyright_xml | – notice: Copyright © 2016 John Wiley & Sons, Ltd. |
DBID | CGR CUY CVF ECM EIF NPM 7X8 |
DOI | 10.1002/jlcr.3413 |
DatabaseName | Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic |
DatabaseTitle | MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic |
DatabaseTitleList | MEDLINE MEDLINE - Academic |
Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: EIF name: MEDLINE url: https://proxy.k.utb.cz/login?url=https://www.webofscience.com/wos/medline/basic-search sourceTypes: Index Database |
DeliveryMethod | fulltext_linktorsrc |
Discipline | Chemistry |
EISSN | 1099-1344 |
EndPage | 363 |
ExternalDocumentID | 27264196 |
Genre | Research Support, Non-U.S. Gov't Journal Article |
GroupedDBID | --- .3N .GA .GJ .Y3 05W 0R~ 10A 1L6 1OB 1OC 1ZS 31~ 33P 3SF 3WU 4.4 50Y 50Z 51W 51X 52M 52N 52O 52P 52S 52T 52U 52W 52X 53G 5GY 5VS 66C 702 7PT 8-0 8-1 8-3 8-4 8-5 8UM 930 A03 AAESR AAEVG AAHHS AANLZ AAONW AASGY AAXRX AAZKR ABCQN ABCUV ABDBF ABEML ABIJN ACAHQ ACBWZ ACCFJ ACCZN ACGFS ACIWK ACNCT ACPOU ACPRK ACSCC ACXBN ACXQS ADBBV ADEOM ADIZJ ADKYN ADMGS ADOZA ADXAS ADZMN AEEZP AEIGN AEIMD AENEX AEQDE AEUQT AEUYR AFBPY AFFPM AFGKR AFPWT AFZJQ AHBTC AI. AITYG AIURR AIWBW AJBDE AJXKR ALAGY ALMA_UNASSIGNED_HOLDINGS ALUQN AMBMR AMYDB ATUGU AUFTA AZBYB AZFZN AZVAB BAFTC BDRZF BFHJK BHBCM BMNLL BMXJE BNHUX BROTX BRXPI BY8 CGR CS3 CUY CVF D-E D-F DCZOG DPXWK DR2 DRFUL DRSTM DU5 EBD EBS ECM EIF EJD F00 F01 F04 F5P FEDTE G-S G.N GNP GODZA GWYGA H.T H.X HBH HF~ HGLYW HHY HHZ HVGLF HZ~ IX1 J0M JPC KQQ LATKE LAW LC2 LC3 LEEKS LITHE LOXES LP6 LP7 LUTES LYRES M6Q MEWTI MK4 MRFUL MRSTM MSFUL MSSTM MXFUL MXSTM N04 N05 N9A NF~ NNB NPM O66 O9- OIG P2P P2W P2X P4D PALCI Q.N Q11 QB0 QRW R.K RIWAO ROL RWI RX1 SAMSI SUPJJ TUS UB1 V2E VH1 W8V W99 WBFHL WBKPD WH7 WIB WIH WIK WJL WOHZO WQJ WRC WUP WWP WXSBR WYISQ XG1 XV2 YCJ ZZTAW ~IA ~WT 7X8 |
ID | FETCH-LOGICAL-p196t-8214c6ae449096fb9a2a5c48c9c1743ab13550264762a2b499455c52098dce8a3 |
IngestDate | Fri Aug 16 04:01:18 EDT 2024 Wed Oct 16 00:57:56 EDT 2024 |
IsPeerReviewed | true |
IsScholarly | true |
Issue | 9 |
Keywords | cetuximab theranostics cancer lutetium-177 yttrium-90 EGFR |
Language | English |
License | Copyright © 2016 John Wiley & Sons, Ltd. |
LinkModel | OpenURL |
MergedId | FETCHMERGED-LOGICAL-p196t-8214c6ae449096fb9a2a5c48c9c1743ab13550264762a2b499455c52098dce8a3 |
Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
PMID | 27264196 |
PQID | 1802477490 |
PQPubID | 23479 |
PageCount | 10 |
ParticipantIDs | proquest_miscellaneous_1802477490 pubmed_primary_27264196 |
PublicationCentury | 2000 |
PublicationDate | 2016-07-01 |
PublicationDateYYYYMMDD | 2016-07-01 |
PublicationDate_xml | – month: 07 year: 2016 text: 2016-07-01 day: 01 |
PublicationDecade | 2010 |
PublicationPlace | England |
PublicationPlace_xml | – name: England |
PublicationTitle | Journal of labelled compounds & radiopharmaceuticals |
PublicationTitleAlternate | J Labelled Comp Radiopharm |
PublicationYear | 2016 |
SSID | ssj0009944 |
Score | 2.2004764 |
Snippet | Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for... |
SourceID | proquest pubmed |
SourceType | Aggregation Database Index Database |
StartPage | 354 |
SubjectTerms | Animals Cell Line, Tumor Cetuximab - chemistry Drug Compounding Immunoconjugates - chemistry Immunoconjugates - pharmacokinetics Isotope Labeling Lutetium - chemistry Mice Molecular Imaging Positron-Emission Tomography Radiochemistry Tissue Distribution Yttrium Radioisotopes - chemistry |
Title | (90) Y/(177) Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation |
URI | https://www.ncbi.nlm.nih.gov/pubmed/27264196 https://search.proquest.com/docview/1802477490 |
Volume | 59 |
hasFullText | 1 |
inHoldings | 1 |
isFullTextHit | |
isPrint | |
link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV1bT9swFLY6eBgvaMA2YIA8CSRQFMjFSWPeEBchBDyMi-Cpsh1XFLVNVZJp4i_xJzknTkyAVRp7iaq4tWufTz4Xn_OZkPXIV6iGUtj94thFfnZXhDx1Q5HAa9nVbYYFzmfn8fEVO7mJblqtp0bWUpHLbfX417qS_5EqvAO5YpXsByRrO4UX8BnkC0-QMDz_ScYbeH6Hfv0t9IGMS3gyyp3TwgXZYkQeo7d58ac3ENLpYSVIBu7vfYGhszIVbizSHl6ZZe58czLYPwZVYSYapbZsMsWsdjRvq8u-Jpi0dlRMVMf7mh5KZJWjjO6awXNryZu0gt8wOSPtQur-6zYAqWm7KFLY4KwaucD-Ss0p-iKF3jEBysa2Rc8kizjXzjVMv49nBM0Ihx_bbFhQUGZXRhpRPzREkfW2XRGJG3jyxh4cGlbqd7rBcM3e99V4G1V38zuw4qNBCZKgDRaiz9-wc5f6vm76RKaDNo8wf_Tg1wtXGeeM1dRVXrBjx0G66eqXk72Y0pq5_EJmK5nRPYOpOdLSw3nyeb9GwgIZbHJvi97ubAKmtmgDUdQiir5F1C59jSfaxBPNM1rjiSKeaANPX8nV0eHl_rFbXc3hjmAeuZsEPlOx0Ixx8IG7kotARIoliit0cYX0wY4F956BrhWBBLeaRZHClKskVToR4TcyNcyGepFQv6u6UrWZkrCA0vcElkp7ifICHemEsyXys160Dvx7PM8SQ50VDx0kL2TgvnBviXw3q9kZGY6WTr3kyxNbfpCZF7CtkKl8XOhVMDBzuVYK9hmDRH5J |
link.rule.ids | 315,786,790,27955,27956 |
linkProvider | Wiley-Blackwell |
openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=%2890%29+Y%2F%28177%29+Lu-labelled+Cetuximab+immunoconjugates%3A+radiochemistry+optimization+to+clinical+dose+formulation&rft.jtitle=Journal+of+labelled+compounds+%26+radiopharmaceuticals&rft.au=Chakravarty%2C+Rubel&rft.au=Chakraborty%2C+Sudipta&rft.au=Sarma%2C+Haladhar+Dev&rft.au=Nair%2C+K+V+Vimalnath&rft.date=2016-07-01&rft.eissn=1099-1344&rft.volume=59&rft.issue=9&rft.spage=354&rft_id=info:doi/10.1002%2Fjlcr.3413&rft_id=info%3Apmid%2F27264196&rft.externalDocID=27264196 |