A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α<sub>V</sub>ß<sub>3</sub> Binder for the Treatment of Multiple Cancer Types
To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an α<sub>V</sub>β<sub>3</sub> integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in th...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/2/391 |
| _version_ | 1797495322771980288 |
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| author | Hans-Georg Lerchen Beatrix Stelte-Ludwig Charlotte Kopitz Melanie Heroult Dmitry Zubov Joerg Willuda Thomas Schlange Antje Kahnert Harvey Wong Raquel Izumi Ahmed Hamdy |
| author_facet | Hans-Georg Lerchen Beatrix Stelte-Ludwig Charlotte Kopitz Melanie Heroult Dmitry Zubov Joerg Willuda Thomas Schlange Antje Kahnert Harvey Wong Raquel Izumi Ahmed Hamdy |
| author_sort | Hans-Georg Lerchen |
| collection | DOAJ |
| description | To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an α<sub>V</sub>β<sub>3</sub> integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the α<sub>V</sub>β<sub>3</sub> binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing α<sub>V</sub>β<sub>3</sub> as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma. |
| first_indexed | 2024-03-10T01:46:12Z |
| format | Article |
| id | doaj.art-6c27678cf6b047208408e246c8964c85 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:46:12Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-6c27678cf6b047208408e246c8964c852023-11-23T13:14:15ZengMDPI AGCancers2072-66942022-01-0114239110.3390/cancers14020391A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α<sub>V</sub>ß<sub>3</sub> Binder for the Treatment of Multiple Cancer TypesHans-Georg Lerchen0Beatrix Stelte-Ludwig1Charlotte Kopitz2Melanie Heroult3Dmitry Zubov4Joerg Willuda5Thomas Schlange6Antje Kahnert7Harvey Wong8Raquel Izumi9Ahmed Hamdy10Vincerx Pharma GmbH, 40789 Monheim am Rhein, GermanyVincerx Pharma GmbH, 40789 Monheim am Rhein, GermanyNuvisan Innovation Campus, 13353 Berlin, GermanyCrop Science Division, Bayer AG, 65926 Frankfurt am Main, GermanyPharmaceuticals R&D, Bayer AG, 42096 Wuppertal, GermanyPharmaceuticals R&D, Bayer AG, 13353 Berlin, GermanyPharmaceuticals R&D, Bayer AG, 42096 Wuppertal, GermanyPharmaceuticals R&D, Bayer AG, 42096 Wuppertal, GermanyVincerx Pharma Inc., Palo Alto, CA 94306, USAVincerx Pharma Inc., Palo Alto, CA 94306, USAVincerx Pharma Inc., Palo Alto, CA 94306, USATo improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an α<sub>V</sub>β<sub>3</sub> integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the α<sub>V</sub>β<sub>3</sub> binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing α<sub>V</sub>β<sub>3</sub> as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma.https://www.mdpi.com/2072-6694/14/2/391α<sub>V</sub>β<sub>3</sub> integrincamptothecin payloadneutrophil elastasesmall molecule–drug conjugateSMDCSN38 derivative |
| spellingShingle | Hans-Georg Lerchen Beatrix Stelte-Ludwig Charlotte Kopitz Melanie Heroult Dmitry Zubov Joerg Willuda Thomas Schlange Antje Kahnert Harvey Wong Raquel Izumi Ahmed Hamdy A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α<sub>V</sub>ß<sub>3</sub> Binder for the Treatment of Multiple Cancer Types Cancers α<sub>V</sub>β<sub>3</sub> integrin camptothecin payload neutrophil elastase small molecule–drug conjugate SMDC SN38 derivative |
| title | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α<sub>V</sub>ß<sub>3</sub> Binder for the Treatment of Multiple Cancer Types |
| title_full | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α<sub>V</sub>ß<sub>3</sub> Binder for the Treatment of Multiple Cancer Types |
| title_fullStr | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α<sub>V</sub>ß<sub>3</sub> Binder for the Treatment of Multiple Cancer Types |
| title_full_unstemmed | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α<sub>V</sub>ß<sub>3</sub> Binder for the Treatment of Multiple Cancer Types |
| title_short | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α<sub>V</sub>ß<sub>3</sub> Binder for the Treatment of Multiple Cancer Types |
| title_sort | small molecule drug conjugate smdc consisting of a modified camptothecin payload linked to an α sub v sub ss sub 3 sub binder for the treatment of multiple cancer types |
| topic | α<sub>V</sub>β<sub>3</sub> integrin camptothecin payload neutrophil elastase small molecule–drug conjugate SMDC SN38 derivative |
| url | https://www.mdpi.com/2072-6694/14/2/391 |
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