Monoclonal antibodies as reversible equilibrium carriers of radiopharmaceuticals

Goodwin, David A.; Meares, Claude F.; Gourichon, David; McTigue, Maureen; McCall, Michael; Frincke, James M.; Stone, Mary R.; Bartholomew, Richard M.; Leung, Julia P.

doi:10.1016/0883-2897(86)90015-2

Cited by 31 publications

(20 citation statements)

References 15 publications

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“…The activation enthalpies and entropies of the four compounds are experimentally identical, despite opposite para-substituent charges (14,17) and vastly different room temperature rate constants (14,18,20). 3 The temperature dependence of the rate constants for 7 appears to parallel 18, 14, 20, and 17.…”

Section: Discussionmentioning

confidence: 87%

Kinetics of the dissociation of indium-(para-substituted-benzyl)ethylenediaminetetraacetic acid hapten analogs from the monoclonal anti-hapten antibody CHA255

Meyer¹,

Fineman²,

Unger³

et al. 1990

Bioconjugate Chem.

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Half-lives were measured for the dissociation of a series of 20 indium-benzyl-EDTA derivatives from a monoclonal antibody that binds to them. Most haptens gave expected monoexponential dissociation curves with half-lives ranging from approximately 8 to approximately 100 min at 22 +/- 1 degree C. Precise (+/- approximately 2.5%) determinations were made using centrifugal ultrafiltration to separate free from bound hapten. A strong pH dependence of the dissociation half-life was found for the two haptens studied. Activation enthalpies were identical (23 +/- 1 kcal/mol) for the dissociation of four haptens, suggesting that, in contrast to individual rate constants, this parameter is insensitive to hapten modification. The dissociation half-lives provided evidence for the location of a positive charge in the binding site, but gave no clear indication of the role of hydrophobic interactions or of steric requirements in hapten binding. While variations in ionic strength had no effect on the dissociation rate, lowering surface tension with dioxane increased the rate somewhat. Three hapten-antibody complexes showed biexponential dissociation rates. It is postulated that this results from distinct conformations of the complex dissociating at different rates. The dissociation rate constant was found to be an extremely sensitive indicator of the hapten-antibody interaction that can be measured very precisely.

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Section: Discussionmentioning

confidence: 87%

Kinetics of the dissociation of indium-(para-substituted-benzyl)ethylenediaminetetraacetic acid hapten analogs from the monoclonal anti-hapten antibody CHA255

Meyer¹,

Fineman²,

Unger³

et al. 1990

Bioconjugate Chem.

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“…To accomplish this, the targeting was first achieved with a bispecific antibody (bsMAb) that binds both to a target antigen as well as the radiometalchelate complex of the effector molecule (Reardan et al, 1985;Goodwin et al, 1986). By separating the targeting steps, the bsMAb does not need to be treated with reagents used for conjugation to a suitable radionuclide, which ensures its immunoreactivity is uncompromised.…”

Section: Pretargeting As a New Paradigmmentioning

confidence: 99%

Novel radiolabeled antibody conjugates

Goldenberg

Sharkey

2007

Oncogene

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This article reviews the development of radioimmunoconjugates as a new class of cancer therapeutics. Numerous conjugates involving different antigen targets, antibody forms, radionuclides and methods of radiochemistry have been studied in the half-century since radioactive antibodies were first used in model systems to selectively target radiation to tumors. Whereas directly conjugated antibodies, fragments and subfragments have shown promise preclinically, the same approaches have not gained success in patients except in radiosensitive hematological neoplasms, or in settings involving minimal or locoregional disease. The separation of tumor targeting from the delivery of the therapeutic radionuclide in a multistep process called pretargeting has the potential to overcome many of the limitations of conventional, or onestep, radioimmunotherapy, with initial preclinical and clinical data showing increased sensitivity, specificity and higher radiation doses delivered. Our particular focus in pretargeting is the use of bispecific, trimeric (three Fab 0 s) constructs made by a new antibody engineering method termed 'dock-and-lock.'

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“…To accomplish this, the targeting was first achieved with a bsmAb that binds to a target antigen as well as to the effector molecule with the radiometal-chelate complex (32,33). By separating the targeting steps, the bs-mAb does not need to be treated with reagents used for conjugation to a suitable radionuclide, which ensures its immunoreactivity is retained.…”

Section: Pretargeting As a New Paradigmmentioning

confidence: 99%

Multifunctional Antibodies by the Dock-and-Lock Method for Improved Cancer Imaging and Therapy by Pretargeting

Goldenberg

Rossi²,

Sharkey³

et al. 2007

J Nucl Med

130

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The Dock-and-Lock (DNL) method, which makes bioactive molecules with multivalency and multifunctionality, is a new approach to develop targeting molecules for improved cancer imaging and therapy. It involves the use of a pair of distinct protein domains involved in the natural association between cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) and A-kinase anchoring proteins (AKAPs). The dimerization and docking domain found in the regulatory subunit of PKA and the anchoring domain (AD) of an interactive AKAP are each attached to a biologic entity, and the resulting derivatives, when combined, readily form a stably tethered complex of a defined composition that fully retains the functions of the individual constituents. The DNL method has generated several trivalent, bispecific, binding proteins, each consisting of 2 identical Fab fragments linked site-specifically to a different Fab fragment. For example, 2 identical Fabs reacting with carcinoembryonic antigen (CEA) are bound to a Fab reacting with a hapten peptide that bears a diagnostic or therapeutic radionuclide. Using a 2-step, pretargeting method that separates the bivalent anti-CEA antibody targeting of tumor from the delivery of the radioactive peptide that is captured by the second Fab of the tri-Fab construct, an improved method of cancer imaging and therapy has been developed and shows very sensitive and specific targeting of CEA-expressing tumors for either diagnostic imaging, such as with immunoSPECT and immunoPET, or radioimmunotherapy. Improved therapeutic efficacy is shown with pretargeting in a pancreatic cancer xenograft model given a tri-Fab to a pancreatic cancer MUC1 and the hapten peptide labeled with 90 Y.

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Monoclonal antibodies as reversible equilibrium carriers of radiopharmaceuticals

Cited by 31 publications

References 15 publications

Kinetics of the dissociation of indium-(para-substituted-benzyl)ethylenediaminetetraacetic acid hapten analogs from the monoclonal anti-hapten antibody CHA255

Kinetics of the dissociation of indium-(para-substituted-benzyl)ethylenediaminetetraacetic acid hapten analogs from the monoclonal anti-hapten antibody CHA255

Novel radiolabeled antibody conjugates

Multifunctional Antibodies by the Dock-and-Lock Method for Improved Cancer Imaging and Therapy by Pretargeting

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