Biological properties of biotin-chelate conjugates for pretargeted diagnosis and therapy with the avidin/biotin system

David A. Goodwin, Claude F. Meares, Maureen Osen

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Three-step pretargeting increases target-to-background ratios in radioimmunodetection and can potentially decrease harmful radiation to normal tissues in radioimmunotherapy. We studied four biotin-chelate conjugates (BCCs) for use in the avidin/biotin pretargeting system. Methods: Pharmacokinetics and biodistribution were studied in normal BALB/c (IA(k)- negative), normal C3H (IA(k) positive) and LS174T tumor-bearing BALB/c severe combined immunodeficient mice. Streptavidin alone and antibody- streptavidin conjugates [monoclonal antibody (MAb) 10-3.6 anti-IA(k) IgG2a] were used. Indium-111- or 88Y-BCCs were given alone intravenously; they were mixed with streptavidin or MAb-streptavidin conjugate and given intravenously; or streptavidin and MAb-streptavidin conjugate were pretargeted, and 2-3, 5 and 21 hr later, BCCs were injected intravenously. Samples were taken 2-3 hr after intravenous injection of labeled BCCs. Results: Three of the four BCCs were rapidly excreted by the kidneys, with <2.5%/g in any organ or tumor at 2-3 hr. Gut excretion eliminated biotinyl- (S)-1-p-aminobenzylethylenediaminetetraacetic acid (EDTA) for use in pretargeting. Ninety percent of BCCs were bound to circulating pretargeted streptavidin at 1-6 hr, and ~15% were bound to pretargeted streptavidin at 24 hr. Kidney uptakes were: preformed streptavidin-BCC given intravenously, ~80%/g (24 hr); streptavidin pretargeted for 2-3 hr, ~60%/g; and streptavidin pretargeted for 5-21 hr, ~10%-20%/g. Kidney uptake was dose- dependent: 0.2, 0.67 and 1.0 nmol of streptavidin pretargeted for 21 hr showed increasing concentrations (24 hr). Uptake of monoclonal anti-IA(k)- streptavidin-BCC complex into spleen ('70% ± 10%/g; p < 0.05) and lymphnodes (10% ± 3.5%/g; p 0.01) was higher in IA(k)-positive C3H mice than it was in IA(k)-negative control BALB/c mice, and it was much higher than that in streptavidin controls. No significant target uptake was seen with anti-IA(k) MAb-streptavidin pretargeted for 3 or 20 hr. Kidney uptake ~20%/g, which was lower than that of streptavidin alone. Conclusion: Three biotinyl chelates bind the diagnostic and therapeutic radiometals 111In and 88Y (and, by analogy, 90Y) with the required in vivo stability and physiological properties for pretargeted diagnosis and therapy. Kidney uptake of streptavidin was decreased by conjugation to MAb. Failure of anti IA(k) MAb- streptavidin conjugate to bind BCC after pretargeting may be due to rapid internalization of MAb-streptavidin-IA(k) complex by the lymphocyte or to endogenous biotin. Either or both of these would make streptavidin unavailable to subsequent BCCs.

Original languageEnglish (US)
Pages (from-to)1813-1818
Number of pages6
JournalJournal of Nuclear Medicine
Volume39
Issue number10
StatePublished - Oct 1998
Externally publishedYes

Fingerprint

Streptavidin
Avidin
Biotin
Therapeutics
Monoclonal Antibodies
Kidney
Radioimmunodetection
Radioimmunotherapy
Indium
SCID Mice

Keywords

  • Indium-111
  • Pretargeting
  • Radioimmunoimaging
  • Radioimmunotherapy
  • Yttrium90

ASJC Scopus subject areas

  • Radiological and Ultrasound Technology

Cite this

Biological properties of biotin-chelate conjugates for pretargeted diagnosis and therapy with the avidin/biotin system. / Goodwin, David A.; Meares, Claude F.; Osen, Maureen.

In: Journal of Nuclear Medicine, Vol. 39, No. 10, 10.1998, p. 1813-1818.

Research output: Contribution to journalArticle

Goodwin, David A. ; Meares, Claude F. ; Osen, Maureen. / Biological properties of biotin-chelate conjugates for pretargeted diagnosis and therapy with the avidin/biotin system. In: Journal of Nuclear Medicine. 1998 ; Vol. 39, No. 10. pp. 1813-1818.
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abstract = "Three-step pretargeting increases target-to-background ratios in radioimmunodetection and can potentially decrease harmful radiation to normal tissues in radioimmunotherapy. We studied four biotin-chelate conjugates (BCCs) for use in the avidin/biotin pretargeting system. Methods: Pharmacokinetics and biodistribution were studied in normal BALB/c (IA(k)- negative), normal C3H (IA(k) positive) and LS174T tumor-bearing BALB/c severe combined immunodeficient mice. Streptavidin alone and antibody- streptavidin conjugates [monoclonal antibody (MAb) 10-3.6 anti-IA(k) IgG2a] were used. Indium-111- or 88Y-BCCs were given alone intravenously; they were mixed with streptavidin or MAb-streptavidin conjugate and given intravenously; or streptavidin and MAb-streptavidin conjugate were pretargeted, and 2-3, 5 and 21 hr later, BCCs were injected intravenously. Samples were taken 2-3 hr after intravenous injection of labeled BCCs. Results: Three of the four BCCs were rapidly excreted by the kidneys, with <2.5{\%}/g in any organ or tumor at 2-3 hr. Gut excretion eliminated biotinyl- (S)-1-p-aminobenzylethylenediaminetetraacetic acid (EDTA) for use in pretargeting. Ninety percent of BCCs were bound to circulating pretargeted streptavidin at 1-6 hr, and ~15{\%} were bound to pretargeted streptavidin at 24 hr. Kidney uptakes were: preformed streptavidin-BCC given intravenously, ~80{\%}/g (24 hr); streptavidin pretargeted for 2-3 hr, ~60{\%}/g; and streptavidin pretargeted for 5-21 hr, ~10{\%}-20{\%}/g. Kidney uptake was dose- dependent: 0.2, 0.67 and 1.0 nmol of streptavidin pretargeted for 21 hr showed increasing concentrations (24 hr). Uptake of monoclonal anti-IA(k)- streptavidin-BCC complex into spleen ('70{\%} ± 10{\%}/g; p < 0.05) and lymphnodes (10{\%} ± 3.5{\%}/g; p 0.01) was higher in IA(k)-positive C3H mice than it was in IA(k)-negative control BALB/c mice, and it was much higher than that in streptavidin controls. No significant target uptake was seen with anti-IA(k) MAb-streptavidin pretargeted for 3 or 20 hr. Kidney uptake ~20{\%}/g, which was lower than that of streptavidin alone. Conclusion: Three biotinyl chelates bind the diagnostic and therapeutic radiometals 111In and 88Y (and, by analogy, 90Y) with the required in vivo stability and physiological properties for pretargeted diagnosis and therapy. Kidney uptake of streptavidin was decreased by conjugation to MAb. Failure of anti IA(k) MAb- streptavidin conjugate to bind BCC after pretargeting may be due to rapid internalization of MAb-streptavidin-IA(k) complex by the lymphocyte or to endogenous biotin. Either or both of these would make streptavidin unavailable to subsequent BCCs.",
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TY - JOUR

T1 - Biological properties of biotin-chelate conjugates for pretargeted diagnosis and therapy with the avidin/biotin system

AU - Goodwin, David A.

AU - Meares, Claude F.

AU - Osen, Maureen

PY - 1998/10

Y1 - 1998/10

N2 - Three-step pretargeting increases target-to-background ratios in radioimmunodetection and can potentially decrease harmful radiation to normal tissues in radioimmunotherapy. We studied four biotin-chelate conjugates (BCCs) for use in the avidin/biotin pretargeting system. Methods: Pharmacokinetics and biodistribution were studied in normal BALB/c (IA(k)- negative), normal C3H (IA(k) positive) and LS174T tumor-bearing BALB/c severe combined immunodeficient mice. Streptavidin alone and antibody- streptavidin conjugates [monoclonal antibody (MAb) 10-3.6 anti-IA(k) IgG2a] were used. Indium-111- or 88Y-BCCs were given alone intravenously; they were mixed with streptavidin or MAb-streptavidin conjugate and given intravenously; or streptavidin and MAb-streptavidin conjugate were pretargeted, and 2-3, 5 and 21 hr later, BCCs were injected intravenously. Samples were taken 2-3 hr after intravenous injection of labeled BCCs. Results: Three of the four BCCs were rapidly excreted by the kidneys, with <2.5%/g in any organ or tumor at 2-3 hr. Gut excretion eliminated biotinyl- (S)-1-p-aminobenzylethylenediaminetetraacetic acid (EDTA) for use in pretargeting. Ninety percent of BCCs were bound to circulating pretargeted streptavidin at 1-6 hr, and ~15% were bound to pretargeted streptavidin at 24 hr. Kidney uptakes were: preformed streptavidin-BCC given intravenously, ~80%/g (24 hr); streptavidin pretargeted for 2-3 hr, ~60%/g; and streptavidin pretargeted for 5-21 hr, ~10%-20%/g. Kidney uptake was dose- dependent: 0.2, 0.67 and 1.0 nmol of streptavidin pretargeted for 21 hr showed increasing concentrations (24 hr). Uptake of monoclonal anti-IA(k)- streptavidin-BCC complex into spleen ('70% ± 10%/g; p < 0.05) and lymphnodes (10% ± 3.5%/g; p 0.01) was higher in IA(k)-positive C3H mice than it was in IA(k)-negative control BALB/c mice, and it was much higher than that in streptavidin controls. No significant target uptake was seen with anti-IA(k) MAb-streptavidin pretargeted for 3 or 20 hr. Kidney uptake ~20%/g, which was lower than that of streptavidin alone. Conclusion: Three biotinyl chelates bind the diagnostic and therapeutic radiometals 111In and 88Y (and, by analogy, 90Y) with the required in vivo stability and physiological properties for pretargeted diagnosis and therapy. Kidney uptake of streptavidin was decreased by conjugation to MAb. Failure of anti IA(k) MAb- streptavidin conjugate to bind BCC after pretargeting may be due to rapid internalization of MAb-streptavidin-IA(k) complex by the lymphocyte or to endogenous biotin. Either or both of these would make streptavidin unavailable to subsequent BCCs.

AB - Three-step pretargeting increases target-to-background ratios in radioimmunodetection and can potentially decrease harmful radiation to normal tissues in radioimmunotherapy. We studied four biotin-chelate conjugates (BCCs) for use in the avidin/biotin pretargeting system. Methods: Pharmacokinetics and biodistribution were studied in normal BALB/c (IA(k)- negative), normal C3H (IA(k) positive) and LS174T tumor-bearing BALB/c severe combined immunodeficient mice. Streptavidin alone and antibody- streptavidin conjugates [monoclonal antibody (MAb) 10-3.6 anti-IA(k) IgG2a] were used. Indium-111- or 88Y-BCCs were given alone intravenously; they were mixed with streptavidin or MAb-streptavidin conjugate and given intravenously; or streptavidin and MAb-streptavidin conjugate were pretargeted, and 2-3, 5 and 21 hr later, BCCs were injected intravenously. Samples were taken 2-3 hr after intravenous injection of labeled BCCs. Results: Three of the four BCCs were rapidly excreted by the kidneys, with <2.5%/g in any organ or tumor at 2-3 hr. Gut excretion eliminated biotinyl- (S)-1-p-aminobenzylethylenediaminetetraacetic acid (EDTA) for use in pretargeting. Ninety percent of BCCs were bound to circulating pretargeted streptavidin at 1-6 hr, and ~15% were bound to pretargeted streptavidin at 24 hr. Kidney uptakes were: preformed streptavidin-BCC given intravenously, ~80%/g (24 hr); streptavidin pretargeted for 2-3 hr, ~60%/g; and streptavidin pretargeted for 5-21 hr, ~10%-20%/g. Kidney uptake was dose- dependent: 0.2, 0.67 and 1.0 nmol of streptavidin pretargeted for 21 hr showed increasing concentrations (24 hr). Uptake of monoclonal anti-IA(k)- streptavidin-BCC complex into spleen ('70% ± 10%/g; p < 0.05) and lymphnodes (10% ± 3.5%/g; p 0.01) was higher in IA(k)-positive C3H mice than it was in IA(k)-negative control BALB/c mice, and it was much higher than that in streptavidin controls. No significant target uptake was seen with anti-IA(k) MAb-streptavidin pretargeted for 3 or 20 hr. Kidney uptake ~20%/g, which was lower than that of streptavidin alone. Conclusion: Three biotinyl chelates bind the diagnostic and therapeutic radiometals 111In and 88Y (and, by analogy, 90Y) with the required in vivo stability and physiological properties for pretargeted diagnosis and therapy. Kidney uptake of streptavidin was decreased by conjugation to MAb. Failure of anti IA(k) MAb- streptavidin conjugate to bind BCC after pretargeting may be due to rapid internalization of MAb-streptavidin-IA(k) complex by the lymphocyte or to endogenous biotin. Either or both of these would make streptavidin unavailable to subsequent BCCs.

KW - Indium-111

KW - Pretargeting

KW - Radioimmunoimaging

KW - Radioimmunotherapy

KW - Yttrium90

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