Characteristics of dimeric (bis) bidentate selective high affinity ligands as HLA-DR10 beta antibody mimics targeting non-Hodgkin's lymphoma

Gerald L Denardo, Saphon Hok, Arutselvan Natarajan, Monique Cosman, Sally J. DeNardo, Felice C Lightstone, Gary R. Mirick, Aina Yuan, Julie Perkins, Vladimir V. Sysko, Joerg Lehmann, Rodney L. Balhorn

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Despite their large size, antibodies have proven to be suitable radioisotope carriers to deliver systemic radiotherapy, often molecular image-based, for lymphoma and leukemia. To mimic antibody (Ab) targeting behavior while decreasing size by 50-100x, a combination of computational and experimental methods were used to generate molecules that bind to unique sites within the HLA-DR epitopic region of Lym-1, an Ab shown effective in patients. Lym-1 Ab mimics (synthetic high afinity ligands; SHALs) were generated and studied in vitro, using live cell binding assays, and/or pharmacokinetic studies over 24 h in xenografted mice given 1 or 20 μg SHAL doses i.v. Multimilligram amounts of each of the dimeric (bis) SHALs were synthesized at high purity, and labeled with indium-111 at high specific activity and purity. These SHALs were selective for HLA-DR and HLA-DR expressing malignant cells and had functional affinities that ranged from 10-9 M (nanomolar) to 10-10 M. Blood clearances ranged from 3.6 to 9.5 h and body clearances ranged from 15.2 to 43.0 h for the 6 bis DOTA-SHALs studied in a mouse model for non-Hodgkin's lymphoma (NHL). While localization was shown in Raji NHL xenografts, biodistribution was influenced by 'sinks' for individual ligands of the SHALs. Highly pure, dimeric mimics for HLA-DR Ab were synthesized, biotinylated and radiolabeled, and showed selectivity in vitro. Pharmacokinetic behavior in mice was influenced by the ligands and by the linker length of the dimeric SHALs. Nanomolar or better functional affinity was observed when a suitably long linker was used to connect the two bidentate SHALs. The concept and methodology are of interest because applicable for targeting most proteins; the SHAL synthetic platform is highly efficient and adaptive.

Original languageEnglish (US)
Pages (from-to)729-740
Number of pages12
JournalInternational Journal of Oncology
Volume31
Issue number4
StatePublished - Oct 2007

Fingerprint

Non-Hodgkin's Lymphoma
HLA-DR Antigens
Ligands
Antibodies
Pharmacokinetics
Indium
Protein Transport
Heterografts
Radioisotopes
Lymphoma
Leukemia
Radiotherapy
HLA-DR10 antigen
In Vitro Techniques

Keywords

  • Antibodies
  • Imaging
  • Leukemia
  • Lymphoma
  • Nanomolecules
  • Treatment

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Characteristics of dimeric (bis) bidentate selective high affinity ligands as HLA-DR10 beta antibody mimics targeting non-Hodgkin's lymphoma. / Denardo, Gerald L; Hok, Saphon; Natarajan, Arutselvan; Cosman, Monique; DeNardo, Sally J.; Lightstone, Felice C; Mirick, Gary R.; Yuan, Aina; Perkins, Julie; Sysko, Vladimir V.; Lehmann, Joerg; Balhorn, Rodney L.

In: International Journal of Oncology, Vol. 31, No. 4, 10.2007, p. 729-740.

Research output: Contribution to journalArticle

Denardo, GL, Hok, S, Natarajan, A, Cosman, M, DeNardo, SJ, Lightstone, FC, Mirick, GR, Yuan, A, Perkins, J, Sysko, VV, Lehmann, J & Balhorn, RL 2007, 'Characteristics of dimeric (bis) bidentate selective high affinity ligands as HLA-DR10 beta antibody mimics targeting non-Hodgkin's lymphoma', International Journal of Oncology, vol. 31, no. 4, pp. 729-740.
Denardo, Gerald L ; Hok, Saphon ; Natarajan, Arutselvan ; Cosman, Monique ; DeNardo, Sally J. ; Lightstone, Felice C ; Mirick, Gary R. ; Yuan, Aina ; Perkins, Julie ; Sysko, Vladimir V. ; Lehmann, Joerg ; Balhorn, Rodney L. / Characteristics of dimeric (bis) bidentate selective high affinity ligands as HLA-DR10 beta antibody mimics targeting non-Hodgkin's lymphoma. In: International Journal of Oncology. 2007 ; Vol. 31, No. 4. pp. 729-740.
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