Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody
Small-molecule ligands specific for tumor-associated surface receptors have wide applications in cancer diagnosis and therapy. Achieving high-affinity binding to the desired target is important for improving detection limits and for increasing therapeutic efficacy. However, the affinity required for...
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| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2014
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| Online Access: | http://hdl.handle.net/1721.1/91642 https://orcid.org/0000-0003-2398-5896 |
| _version_ | 1826190213203886080 |
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| author | Rhoden, John J. Ruiz-Yi, Benjamin Wittrup, Karl Dane Frangioni, John V. Orcutt, Kelly Davis |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Rhoden, John J. Ruiz-Yi, Benjamin Wittrup, Karl Dane Frangioni, John V. Orcutt, Kelly Davis |
| author_sort | Rhoden, John J. |
| collection | MIT |
| description | Small-molecule ligands specific for tumor-associated surface receptors have wide applications in cancer diagnosis and therapy. Achieving high-affinity binding to the desired target is important for improving detection limits and for increasing therapeutic efficacy. However, the affinity required for maximal binding and retention remains unknown. Here, we present a systematic study of the effect of small-molecule affinity on tumor uptake in vivo with affinities spanning a range of three orders of magnitude. A pretargeted bispecific antibody with different binding affinities to different DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based small molecules is used as a receptor proxy. In this particular system targeting carcinoembryonic antigen, a small-molecule–binding affinity of 400 pmol/L was sufficient to achieve maximal tumor targeting, and an improvement in affinity to 10 pmol/L showed no significant improvement in tumor uptake at 24 hours postinjection. We derive a simple mathematical model of tumor targeting using measurable parameters that correlates well with experimental observations. We use relations derived from the model to develop design criteria for the future development of small-molecule agents for targeted cancer therapeutics. |
| first_indexed | 2024-09-23T08:36:48Z |
| format | Article |
| id | mit-1721.1/91642 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:36:48Z |
| publishDate | 2014 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/916422022-09-23T13:16:29Z Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody Rhoden, John J. Ruiz-Yi, Benjamin Wittrup, Karl Dane Frangioni, John V. Orcutt, Kelly Davis Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Rhoden, John J. Ruiz-Yi, Benjamin Wittrup, Karl Dane Orcutt, Kelly Davis Small-molecule ligands specific for tumor-associated surface receptors have wide applications in cancer diagnosis and therapy. Achieving high-affinity binding to the desired target is important for improving detection limits and for increasing therapeutic efficacy. However, the affinity required for maximal binding and retention remains unknown. Here, we present a systematic study of the effect of small-molecule affinity on tumor uptake in vivo with affinities spanning a range of three orders of magnitude. A pretargeted bispecific antibody with different binding affinities to different DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based small molecules is used as a receptor proxy. In this particular system targeting carcinoembryonic antigen, a small-molecule–binding affinity of 400 pmol/L was sufficient to achieve maximal tumor targeting, and an improvement in affinity to 10 pmol/L showed no significant improvement in tumor uptake at 24 hours postinjection. We derive a simple mathematical model of tumor targeting using measurable parameters that correlates well with experimental observations. We use relations derived from the model to develop design criteria for the future development of small-molecule agents for targeted cancer therapeutics. National Science Foundation (U.S.). Graduate Research Fellowship Program National Institutes of Health (U.S.) (Grant R01-CA-101830) 2014-11-20T14:50:02Z 2014-11-20T14:50:02Z 2012-04 2012-02 Article http://purl.org/eprint/type/JournalArticle 1535-7163 1538-8514 http://hdl.handle.net/1721.1/91642 Orcutt, K. D., J. J. Rhoden, B. Ruiz-Yi, J. V. Frangioni, and K. D. Wittrup. “Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody.” Molecular Cancer Therapeutics 11, no. 6 (April 5, 2012): 1365–1372. https://orcid.org/0000-0003-2398-5896 en_US http://dx.doi.org/10.1158/1535-7163.mct-11-0764 Molecular Cancer Therapeutics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research PMC |
| spellingShingle | Rhoden, John J. Ruiz-Yi, Benjamin Wittrup, Karl Dane Frangioni, John V. Orcutt, Kelly Davis Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody |
| title | Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody |
| title_full | Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody |
| title_fullStr | Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody |
| title_full_unstemmed | Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody |
| title_short | Effect of Small-Molecule-Binding Affinity on Tumor Uptake In Vivo: A Systematic Study Using a Pretargeted Bispecific Antibody |
| title_sort | effect of small molecule binding affinity on tumor uptake in vivo a systematic study using a pretargeted bispecific antibody |
| url | http://hdl.handle.net/1721.1/91642 https://orcid.org/0000-0003-2398-5896 |
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