Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors
Abstract Antibody-drug conjugates (ADCs) are increasingly used in clinic for multiple indications and may improve upon the activity of parental antibodies by delivering cytotoxic payloads into target cells. This activity is predicated upon internalization to release the cytotoxic payloads intracellu...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07439-0 |
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| author | Ezequiel J. Tolosa Lin Yang Jennifer Ayers-Ringler Shinichiro Suzuki Jayapal Reddy Mallareddy Janet Schaefer-Klein Mitesh Borad Farhad Kosari Amarnath Natarajan Aaron S. Mansfield |
| author_facet | Ezequiel J. Tolosa Lin Yang Jennifer Ayers-Ringler Shinichiro Suzuki Jayapal Reddy Mallareddy Janet Schaefer-Klein Mitesh Borad Farhad Kosari Amarnath Natarajan Aaron S. Mansfield |
| author_sort | Ezequiel J. Tolosa |
| collection | DOAJ |
| description | Abstract Antibody-drug conjugates (ADCs) are increasingly used in clinic for multiple indications and may improve upon the activity of parental antibodies by delivering cytotoxic payloads into target cells. This activity is predicated upon internalization to release the cytotoxic payloads intracellularly. Since binding of ADCs to their cell surface targets does not guarantee their internalization, we hypothesize that proteolysis targeting chimeras (PROTACs) could improve the activity of ADCs through forced internalization. We show that PROTACs improve internalization of antibodies or their derivative antibody drug conjugates when both agents target the same oncogenic cell surface proteins (EGFR, HER2 or MET) by 1.4-1.9 fold in most models. PROTACs also significantly enhance cytotoxicity with HER2-targeting ADCs. These effects depend on dynamin and proteolysis. This application of PROTACs may impact the use of ADCs and provides a rationale to combine these agents in clinical trials. |
| format | Article |
| id | doaj-art-33e0d94641b847988d93ef8c9d61b9ba |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-33e0d94641b847988d93ef8c9d61b9ba2025-01-05T12:43:21ZengNature PortfolioCommunications Biology2399-36422024-12-017111010.1038/s42003-024-07439-0Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptorsEzequiel J. Tolosa0Lin Yang1Jennifer Ayers-Ringler2Shinichiro Suzuki3Jayapal Reddy Mallareddy4Janet Schaefer-Klein5Mitesh Borad6Farhad Kosari7Amarnath Natarajan8Aaron S. Mansfield9Mayo ClinicMayo ClinicMayo ClinicMayo ClinicEppley Institute for Cancer Research, University of Nebraska Medical CenterMayo ClinicMayo ClinicMayo ClinicEppley Institute for Cancer Research, University of Nebraska Medical CenterMayo ClinicAbstract Antibody-drug conjugates (ADCs) are increasingly used in clinic for multiple indications and may improve upon the activity of parental antibodies by delivering cytotoxic payloads into target cells. This activity is predicated upon internalization to release the cytotoxic payloads intracellularly. Since binding of ADCs to their cell surface targets does not guarantee their internalization, we hypothesize that proteolysis targeting chimeras (PROTACs) could improve the activity of ADCs through forced internalization. We show that PROTACs improve internalization of antibodies or their derivative antibody drug conjugates when both agents target the same oncogenic cell surface proteins (EGFR, HER2 or MET) by 1.4-1.9 fold in most models. PROTACs also significantly enhance cytotoxicity with HER2-targeting ADCs. These effects depend on dynamin and proteolysis. This application of PROTACs may impact the use of ADCs and provides a rationale to combine these agents in clinical trials.https://doi.org/10.1038/s42003-024-07439-0 |
| spellingShingle | Ezequiel J. Tolosa Lin Yang Jennifer Ayers-Ringler Shinichiro Suzuki Jayapal Reddy Mallareddy Janet Schaefer-Klein Mitesh Borad Farhad Kosari Amarnath Natarajan Aaron S. Mansfield Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors Communications Biology |
| title | Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors |
| title_full | Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors |
| title_fullStr | Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors |
| title_full_unstemmed | Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors |
| title_short | Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors |
| title_sort | proteolysis targeting chimera protac driven antibody internalization of oncogenic cell surface receptors |
| url | https://doi.org/10.1038/s42003-024-07439-0 |
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