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Immunology

Delivery of Radionuclides to Pretargeted Monoclonal Antibodies Using Dihydrofolate Reductase and Methotrexate in an Affinity System

Gregory A. Hawkins, Richard P. McCabe, Chong-Ho Kim, Ramaswamy Subramanian, Reinhard Bredehorst, Gregory A. McCullers, Carl-Wilhelm Vogel, Michael G. Hanna Jr. and Nicholas Pomato
Gregory A. Hawkins
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Richard P. McCabe
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Chong-Ho Kim
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Ramaswamy Subramanian
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Reinhard Bredehorst
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Gregory A. McCullers
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Carl-Wilhelm Vogel
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Michael G. Hanna Jr.
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Nicholas Pomato
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DOI:  Published May 1993
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Abstract

A novel affinity system for a two-phase delivery of radionuclides to tumor cells has been developed. In the first phase, a nontoxic bivalent monoclonal antibody conjugated to an enzyme is targeted to the tumor cells. In the second phase, a radionuclide-derivatized enzyme inhibitor, specific for the enzyme conjugated to the antibody, is administered. The model system selected for this study is the recombinant human enzyme dihydrofolate reductase (rhDHFR) and its high-affinity competitive inhibitor methotrexate (MTX). MTX was labeled with a radionuclide by covalent attachment of diethylenetriaminepentaacetic acid (DTPA) complexed with 111In. Using the γ-carboxyl residue of MTX for the attachment of DTPA, binding of the inhibitor to rhDHFR was not affected. The inhibitory activities of nonderivatized MTX and DTPA-MTX were indistinguishable. Human K562 erythroleukemia cells were used to evaluate under in vitro conditions the DHFR-MTX affinity system for the delivery of 111In-labeled DTPA-MTX to pretargeted α-transferrin receptor antibody-rhDHFR conjugates (α-TFR-DHFR). The data demonstrate that the delivery of 111In is dose dependent and highly specific. Under saturating conditions, binding of 111In-DTPA-MTX to α-TFR-DHFR-treated cells was 14-fold higher than to cells treated with nonconjugated α-TFR antibody. Further experiments indicated that the low level of nonspecific binding of 111In-DTPA-MTX was comparable to that of 111In-DTPA, known for its complete extracellular distribution and rapid clearance through the kidneys. Based on the data of this study, antibody-conjugated rhDHFR and radionuclide-labeled DTPA-MTX complexes provide components for an alternative radioimmunotherapeutic approach that can be expected to result in improved tumor tissue ratios of both the targeting moiety and the radionuclide-labeled derivative as compared to current approaches.

Footnotes

  • ↵3 To whom requests for reprints should be addressed, at Organon Teknika Biotechnology Research Institute, 1330A Piccard Drive, Rockville, MD 20850.

  • Received November 6, 1992.
  • Accepted March 12, 1993.
  • ©1993 American Association for Cancer Research.
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May 1993
Volume 53, Issue 10
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Delivery of Radionuclides to Pretargeted Monoclonal Antibodies Using Dihydrofolate Reductase and Methotrexate in an Affinity System
Gregory A. Hawkins, Richard P. McCabe, Chong-Ho Kim, Ramaswamy Subramanian, Reinhard Bredehorst, Gregory A. McCullers, Carl-Wilhelm Vogel, Michael G. Hanna Jr. and Nicholas Pomato
Cancer Res May 15 1993 (53) (10) 2368-2373;

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Delivery of Radionuclides to Pretargeted Monoclonal Antibodies Using Dihydrofolate Reductase and Methotrexate in an Affinity System
Gregory A. Hawkins, Richard P. McCabe, Chong-Ho Kim, Ramaswamy Subramanian, Reinhard Bredehorst, Gregory A. McCullers, Carl-Wilhelm Vogel, Michael G. Hanna Jr. and Nicholas Pomato
Cancer Res May 15 1993 (53) (10) 2368-2373;
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