Synthesis and radiolabeling of selective high-affinity ligands designed to target non-Hodgkin's lymphoma and leukemia

Saphon Hok, Arutselvan Natarajan, Rod Balhorn, Sally J. DeNardo, Gerald L Denardo, Julie Perkins

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Selective high-affinity ligands (SHALs) were synthesized as molecular targeting agents for HLA-DR10, a cell surface receptor upregulated on malignant B-cell lymphocytes in non-Hodgkin's lymphoma and leukemia. SHALs are designed to mimic the affinity and selectivity of Lym-1, an antibody that binds to the β-subunit of HLA-DR10. To bind selectively to HLA-DR10, SHALs were constructed to bind to two adjacent pockets on the surface of the β-subunit of HLA-DR10 located within an epitope recognized by the Lym-1 antibody. A series of multivalent SHALs with molecular masses of 1500-3000 Da were synthesized using solid/polymer-supported synthesis on chlorotrityl chloride resin in 50-80% yield. To enable their use as radionuclide carriers in mouse studies, SHALs were conjugated to DOTA in a solution-phase reaction with 70-100% yield. 57Co/CoCl2 titrations revealed that 50-60% of the DOTA in the DOTA-conjugated SHALs was available for radiometal chelation. These DOTA-SHALs were labeled with 111In and used to carry out pharmacokinetic studies in mice. Radiolabeling reactions of DOTA-SHALs, with exactly one DOTA entity per targeting SHAL molecule, yielded products with greater than 90% radiochemical purity and specific activities ranging from 97 to 150 μCi/μg.

Original languageEnglish (US)
Pages (from-to)912-921
Number of pages10
JournalBioconjugate Chemistry
Volume18
Issue number3
DOIs
StatePublished - May 2007

Fingerprint

Non-Hodgkin's Lymphoma
Leukemia
Ligands
Antibodies
Epitopes
Pharmacokinetics
Lymphocytes
Cell Surface Receptors
Molecular mass
Chelation
Titration
Radioisotopes
Chlorides
Polymers
B-Lymphocytes
Resins
Cells
Molecules
HLA-DR10 antigen

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Clinical Biochemistry
  • Chemistry(all)
  • Organic Chemistry

Cite this

Synthesis and radiolabeling of selective high-affinity ligands designed to target non-Hodgkin's lymphoma and leukemia. / Hok, Saphon; Natarajan, Arutselvan; Balhorn, Rod; DeNardo, Sally J.; Denardo, Gerald L; Perkins, Julie.

In: Bioconjugate Chemistry, Vol. 18, No. 3, 05.2007, p. 912-921.

Research output: Contribution to journalArticle

Hok, Saphon ; Natarajan, Arutselvan ; Balhorn, Rod ; DeNardo, Sally J. ; Denardo, Gerald L ; Perkins, Julie. / Synthesis and radiolabeling of selective high-affinity ligands designed to target non-Hodgkin's lymphoma and leukemia. In: Bioconjugate Chemistry. 2007 ; Vol. 18, No. 3. pp. 912-921.
@article{0e2772b775934ca1b7e0c81e5c5df26a,
title = "Synthesis and radiolabeling of selective high-affinity ligands designed to target non-Hodgkin's lymphoma and leukemia",
abstract = "Selective high-affinity ligands (SHALs) were synthesized as molecular targeting agents for HLA-DR10, a cell surface receptor upregulated on malignant B-cell lymphocytes in non-Hodgkin's lymphoma and leukemia. SHALs are designed to mimic the affinity and selectivity of Lym-1, an antibody that binds to the β-subunit of HLA-DR10. To bind selectively to HLA-DR10, SHALs were constructed to bind to two adjacent pockets on the surface of the β-subunit of HLA-DR10 located within an epitope recognized by the Lym-1 antibody. A series of multivalent SHALs with molecular masses of 1500-3000 Da were synthesized using solid/polymer-supported synthesis on chlorotrityl chloride resin in 50-80{\%} yield. To enable their use as radionuclide carriers in mouse studies, SHALs were conjugated to DOTA in a solution-phase reaction with 70-100{\%} yield. 57Co/CoCl2 titrations revealed that 50-60{\%} of the DOTA in the DOTA-conjugated SHALs was available for radiometal chelation. These DOTA-SHALs were labeled with 111In and used to carry out pharmacokinetic studies in mice. Radiolabeling reactions of DOTA-SHALs, with exactly one DOTA entity per targeting SHAL molecule, yielded products with greater than 90{\%} radiochemical purity and specific activities ranging from 97 to 150 μCi/μg.",
author = "Saphon Hok and Arutselvan Natarajan and Rod Balhorn and DeNardo, {Sally J.} and Denardo, {Gerald L} and Julie Perkins",
year = "2007",
month = "5",
doi = "10.1021/bc060305o",
language = "English (US)",
volume = "18",
pages = "912--921",
journal = "Bioconjugate Chemistry",
issn = "1043-1802",
publisher = "American Chemical Society",
number = "3",

}

TY - JOUR

T1 - Synthesis and radiolabeling of selective high-affinity ligands designed to target non-Hodgkin's lymphoma and leukemia

AU - Hok, Saphon

AU - Natarajan, Arutselvan

AU - Balhorn, Rod

AU - DeNardo, Sally J.

AU - Denardo, Gerald L

AU - Perkins, Julie

PY - 2007/5

Y1 - 2007/5

N2 - Selective high-affinity ligands (SHALs) were synthesized as molecular targeting agents for HLA-DR10, a cell surface receptor upregulated on malignant B-cell lymphocytes in non-Hodgkin's lymphoma and leukemia. SHALs are designed to mimic the affinity and selectivity of Lym-1, an antibody that binds to the β-subunit of HLA-DR10. To bind selectively to HLA-DR10, SHALs were constructed to bind to two adjacent pockets on the surface of the β-subunit of HLA-DR10 located within an epitope recognized by the Lym-1 antibody. A series of multivalent SHALs with molecular masses of 1500-3000 Da were synthesized using solid/polymer-supported synthesis on chlorotrityl chloride resin in 50-80% yield. To enable their use as radionuclide carriers in mouse studies, SHALs were conjugated to DOTA in a solution-phase reaction with 70-100% yield. 57Co/CoCl2 titrations revealed that 50-60% of the DOTA in the DOTA-conjugated SHALs was available for radiometal chelation. These DOTA-SHALs were labeled with 111In and used to carry out pharmacokinetic studies in mice. Radiolabeling reactions of DOTA-SHALs, with exactly one DOTA entity per targeting SHAL molecule, yielded products with greater than 90% radiochemical purity and specific activities ranging from 97 to 150 μCi/μg.

AB - Selective high-affinity ligands (SHALs) were synthesized as molecular targeting agents for HLA-DR10, a cell surface receptor upregulated on malignant B-cell lymphocytes in non-Hodgkin's lymphoma and leukemia. SHALs are designed to mimic the affinity and selectivity of Lym-1, an antibody that binds to the β-subunit of HLA-DR10. To bind selectively to HLA-DR10, SHALs were constructed to bind to two adjacent pockets on the surface of the β-subunit of HLA-DR10 located within an epitope recognized by the Lym-1 antibody. A series of multivalent SHALs with molecular masses of 1500-3000 Da were synthesized using solid/polymer-supported synthesis on chlorotrityl chloride resin in 50-80% yield. To enable their use as radionuclide carriers in mouse studies, SHALs were conjugated to DOTA in a solution-phase reaction with 70-100% yield. 57Co/CoCl2 titrations revealed that 50-60% of the DOTA in the DOTA-conjugated SHALs was available for radiometal chelation. These DOTA-SHALs were labeled with 111In and used to carry out pharmacokinetic studies in mice. Radiolabeling reactions of DOTA-SHALs, with exactly one DOTA entity per targeting SHAL molecule, yielded products with greater than 90% radiochemical purity and specific activities ranging from 97 to 150 μCi/μg.

UR - http://www.scopus.com/inward/record.url?scp=34347353345&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34347353345&partnerID=8YFLogxK

U2 - 10.1021/bc060305o

DO - 10.1021/bc060305o

M3 - Article

C2 - 17373772

AN - SCOPUS:34347353345

VL - 18

SP - 912

EP - 921

JO - Bioconjugate Chemistry

JF - Bioconjugate Chemistry

SN - 1043-1802

IS - 3

ER -