Nanomolecular HLA-DR10 antibody mimics: A potent system for molecular targeted therapy and imaging

Gerald L Denardo, Arutselvan Natarajan, Saphon Hok, Gary Mirick, Sally J. DeNardo, Michele Corzett, Vladimir Sysko, Joerg Lehmann, Laurel A Beckett, Rod Balhorn

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

To mimic the molecular specificity and cell selectivity of monoclonal antibody (mAb) binding while decreasing size, nanomolecules (selective high-affinity ligands; SHALs), based on in silico modeling, have been created to bind to human leukocyte antigen-DR (HLA-DR10), a signaling receptor protein upregulated on the malignant B-lymphocytes of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. SHALs were synthesized with a biotin or DOTA chelate (1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′ ′-tetraacetic acid), using a solid-phase lysine-polyethyleneglycol backbone to link sets of ligands shown previously to bind to HLA-DR10. Using cell-binding and death assays and confocal microscopy, SHAL uptake, residualization, and cytocidal activity were evaluated in HLA-DR10 expressing and nonexpressing live, human lymphoma cell lines. All of the SHALs tested were selective for, and accumulated in, expressing cells. Reflecting binding to HLA-DR10 inside the cells, SHALs having the Ct ligand (3-(2-([3-chloro-5- trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3-oxopropanionic acid) residualized in expressing cells greater than 179 times more than accountable by cell-surface membrane HLA-DR10. Confocal microscopy confirmed the intracellular residualization of these SHALs. Importantly, SHALs with a Ct ligand had direct cytocidal activity, similar in potency to that of Lym-1 mAb and rituximab, selectively for HLA-DR10 expressing lymphoma cells and xenografts. The results show that SHALs containing the Ct ligand residualize intracellularly and have cytocidal effects mediated by HLA-DR10. These SHALs have extraordinary potential as novel molecules for the selective targeting of lymphoma and leukemia for molecular therapy and imaging. Further, these SHALs can be used to transport and residualize cytotoxic agents near critical sites inside these malignant cells.

Original languageEnglish (US)
Pages (from-to)783-795
Number of pages13
JournalCancer Biotherapy and Radiopharmaceuticals
Volume23
Issue number6
DOIs
StatePublished - Dec 1 2008

Fingerprint

Molecular Targeted Therapy
Antibodies
Ligands
Lymphoma
Confocal Microscopy
Molecular Imaging
Acids
Cytotoxins
B-Cell Chronic Lymphocytic Leukemia
HLA Antigens
HLA-DR10 antigen
Heterografts
Computer Simulation
Non-Hodgkin's Lymphoma
Lysine
Leukemia
B-Lymphocytes
Cell Death
Monoclonal Antibodies
Cell Membrane

Keywords

  • Antibodies
  • HLA-DR
  • Imaging
  • Ligands
  • Lymphoma
  • Nanomolecules
  • Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology

Cite this

Nanomolecular HLA-DR10 antibody mimics : A potent system for molecular targeted therapy and imaging. / Denardo, Gerald L; Natarajan, Arutselvan; Hok, Saphon; Mirick, Gary; DeNardo, Sally J.; Corzett, Michele; Sysko, Vladimir; Lehmann, Joerg; Beckett, Laurel A; Balhorn, Rod.

In: Cancer Biotherapy and Radiopharmaceuticals, Vol. 23, No. 6, 01.12.2008, p. 783-795.

Research output: Contribution to journalArticle

Denardo, GL, Natarajan, A, Hok, S, Mirick, G, DeNardo, SJ, Corzett, M, Sysko, V, Lehmann, J, Beckett, LA & Balhorn, R 2008, 'Nanomolecular HLA-DR10 antibody mimics: A potent system for molecular targeted therapy and imaging', Cancer Biotherapy and Radiopharmaceuticals, vol. 23, no. 6, pp. 783-795. https://doi.org/10.1089/cbr.2008.0589
Denardo, Gerald L ; Natarajan, Arutselvan ; Hok, Saphon ; Mirick, Gary ; DeNardo, Sally J. ; Corzett, Michele ; Sysko, Vladimir ; Lehmann, Joerg ; Beckett, Laurel A ; Balhorn, Rod. / Nanomolecular HLA-DR10 antibody mimics : A potent system for molecular targeted therapy and imaging. In: Cancer Biotherapy and Radiopharmaceuticals. 2008 ; Vol. 23, No. 6. pp. 783-795.
@article{3dd908c5c6f34fd6b41dce4e468c520e,
title = "Nanomolecular HLA-DR10 antibody mimics: A potent system for molecular targeted therapy and imaging",
abstract = "To mimic the molecular specificity and cell selectivity of monoclonal antibody (mAb) binding while decreasing size, nanomolecules (selective high-affinity ligands; SHALs), based on in silico modeling, have been created to bind to human leukocyte antigen-DR (HLA-DR10), a signaling receptor protein upregulated on the malignant B-lymphocytes of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. SHALs were synthesized with a biotin or DOTA chelate (1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′ ′-tetraacetic acid), using a solid-phase lysine-polyethyleneglycol backbone to link sets of ligands shown previously to bind to HLA-DR10. Using cell-binding and death assays and confocal microscopy, SHAL uptake, residualization, and cytocidal activity were evaluated in HLA-DR10 expressing and nonexpressing live, human lymphoma cell lines. All of the SHALs tested were selective for, and accumulated in, expressing cells. Reflecting binding to HLA-DR10 inside the cells, SHALs having the Ct ligand (3-(2-([3-chloro-5- trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3-oxopropanionic acid) residualized in expressing cells greater than 179 times more than accountable by cell-surface membrane HLA-DR10. Confocal microscopy confirmed the intracellular residualization of these SHALs. Importantly, SHALs with a Ct ligand had direct cytocidal activity, similar in potency to that of Lym-1 mAb and rituximab, selectively for HLA-DR10 expressing lymphoma cells and xenografts. The results show that SHALs containing the Ct ligand residualize intracellularly and have cytocidal effects mediated by HLA-DR10. These SHALs have extraordinary potential as novel molecules for the selective targeting of lymphoma and leukemia for molecular therapy and imaging. Further, these SHALs can be used to transport and residualize cytotoxic agents near critical sites inside these malignant cells.",
keywords = "Antibodies, HLA-DR, Imaging, Ligands, Lymphoma, Nanomolecules, Therapy",
author = "Denardo, {Gerald L} and Arutselvan Natarajan and Saphon Hok and Gary Mirick and DeNardo, {Sally J.} and Michele Corzett and Vladimir Sysko and Joerg Lehmann and Beckett, {Laurel A} and Rod Balhorn",
year = "2008",
month = "12",
day = "1",
doi = "10.1089/cbr.2008.0589",
language = "English (US)",
volume = "23",
pages = "783--795",
journal = "Cancer Biotherapy and Radiopharmaceuticals",
issn = "1084-9785",
publisher = "Mary Ann Liebert Inc.",
number = "6",

}

TY - JOUR

T1 - Nanomolecular HLA-DR10 antibody mimics

T2 - A potent system for molecular targeted therapy and imaging

AU - Denardo, Gerald L

AU - Natarajan, Arutselvan

AU - Hok, Saphon

AU - Mirick, Gary

AU - DeNardo, Sally J.

AU - Corzett, Michele

AU - Sysko, Vladimir

AU - Lehmann, Joerg

AU - Beckett, Laurel A

AU - Balhorn, Rod

PY - 2008/12/1

Y1 - 2008/12/1

N2 - To mimic the molecular specificity and cell selectivity of monoclonal antibody (mAb) binding while decreasing size, nanomolecules (selective high-affinity ligands; SHALs), based on in silico modeling, have been created to bind to human leukocyte antigen-DR (HLA-DR10), a signaling receptor protein upregulated on the malignant B-lymphocytes of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. SHALs were synthesized with a biotin or DOTA chelate (1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′ ′-tetraacetic acid), using a solid-phase lysine-polyethyleneglycol backbone to link sets of ligands shown previously to bind to HLA-DR10. Using cell-binding and death assays and confocal microscopy, SHAL uptake, residualization, and cytocidal activity were evaluated in HLA-DR10 expressing and nonexpressing live, human lymphoma cell lines. All of the SHALs tested were selective for, and accumulated in, expressing cells. Reflecting binding to HLA-DR10 inside the cells, SHALs having the Ct ligand (3-(2-([3-chloro-5- trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3-oxopropanionic acid) residualized in expressing cells greater than 179 times more than accountable by cell-surface membrane HLA-DR10. Confocal microscopy confirmed the intracellular residualization of these SHALs. Importantly, SHALs with a Ct ligand had direct cytocidal activity, similar in potency to that of Lym-1 mAb and rituximab, selectively for HLA-DR10 expressing lymphoma cells and xenografts. The results show that SHALs containing the Ct ligand residualize intracellularly and have cytocidal effects mediated by HLA-DR10. These SHALs have extraordinary potential as novel molecules for the selective targeting of lymphoma and leukemia for molecular therapy and imaging. Further, these SHALs can be used to transport and residualize cytotoxic agents near critical sites inside these malignant cells.

AB - To mimic the molecular specificity and cell selectivity of monoclonal antibody (mAb) binding while decreasing size, nanomolecules (selective high-affinity ligands; SHALs), based on in silico modeling, have been created to bind to human leukocyte antigen-DR (HLA-DR10), a signaling receptor protein upregulated on the malignant B-lymphocytes of non-Hodgkin's lymphoma and chronic lymphocytic leukemia. SHALs were synthesized with a biotin or DOTA chelate (1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′ ′-tetraacetic acid), using a solid-phase lysine-polyethyleneglycol backbone to link sets of ligands shown previously to bind to HLA-DR10. Using cell-binding and death assays and confocal microscopy, SHAL uptake, residualization, and cytocidal activity were evaluated in HLA-DR10 expressing and nonexpressing live, human lymphoma cell lines. All of the SHALs tested were selective for, and accumulated in, expressing cells. Reflecting binding to HLA-DR10 inside the cells, SHALs having the Ct ligand (3-(2-([3-chloro-5- trifluoromethyl)-2-pyridinyl]oxy)-anilino)-3-oxopropanionic acid) residualized in expressing cells greater than 179 times more than accountable by cell-surface membrane HLA-DR10. Confocal microscopy confirmed the intracellular residualization of these SHALs. Importantly, SHALs with a Ct ligand had direct cytocidal activity, similar in potency to that of Lym-1 mAb and rituximab, selectively for HLA-DR10 expressing lymphoma cells and xenografts. The results show that SHALs containing the Ct ligand residualize intracellularly and have cytocidal effects mediated by HLA-DR10. These SHALs have extraordinary potential as novel molecules for the selective targeting of lymphoma and leukemia for molecular therapy and imaging. Further, these SHALs can be used to transport and residualize cytotoxic agents near critical sites inside these malignant cells.

KW - Antibodies

KW - HLA-DR

KW - Imaging

KW - Ligands

KW - Lymphoma

KW - Nanomolecules

KW - Therapy

UR - http://www.scopus.com/inward/record.url?scp=58549116710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58549116710&partnerID=8YFLogxK

U2 - 10.1089/cbr.2008.0589

DO - 10.1089/cbr.2008.0589

M3 - Article

C2 - 20443696

AN - SCOPUS:58549116710

VL - 23

SP - 783

EP - 795

JO - Cancer Biotherapy and Radiopharmaceuticals

JF - Cancer Biotherapy and Radiopharmaceuticals

SN - 1084-9785

IS - 6

ER -