Cancer cell killing by target antigen engagement with engineered complementary intracellular antibody single domains fused to pro-caspase3
<p>Many tumour causing proteins, such as those expressed after chromosomal translocations or from point mutations, are intracellular and are not enzymes <em>per se</em> amenable to conventional drug targeting. We previously demonstrated an approach (<u>A</u>ntibody-anti...
| Main Authors: | , , |
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| 格式: | Journal article |
| 語言: | English |
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Nature Research
2019
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| _version_ | 1826281079627055104 |
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| author | Chambers, J Brend, T Rabbitts, T |
| author_facet | Chambers, J Brend, T Rabbitts, T |
| author_sort | Chambers, J |
| collection | OXFORD |
| description | <p>Many tumour causing proteins, such as those expressed after chromosomal translocations or from point mutations, are intracellular and are not enzymes <em>per se</em> amenable to conventional drug targeting. We previously demonstrated an approach (<u>A</u>ntibody-antigen <u>I</u>nteraction <u>D</u>ependent <u>A</u>poptosis (AIDA)) whereby a single anti-β-galactosidase intracellular single chain Fv antibody fragment, fused to inactive procaspase-3, induced auto-activation of caspase-3 after binding to the tetrameric β-galactosidase protein. We now demonstrate that co-expressing an anti-RAS heavy chain single VH domain, that binds to mutant RAS several thousand times more strongly than to wild type RAS, with a complementary light chain VL domain, caused programmed cell death (PCD) in mutant RAS expressing cells when each variable region is fused to procaspase-3. The effect requires binding of both anti-RAS variable region fragments and is RAS-specific, producing a tri-molecular complex that auto-activates the caspase pathway leading to cell death. AIDA can be generally applicable for any target protein inside cells by involving appropriate pairs of antigen-specific intracellular antibodies.</p> |
| first_indexed | 2024-03-07T00:23:23Z |
| format | Journal article |
| id | oxford-uuid:7d4b4421-a567-485c-b2c3-ede611dc0b8d |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T00:23:23Z |
| publishDate | 2019 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:7d4b4421-a567-485c-b2c3-ede611dc0b8d2022-03-26T21:02:45ZCancer cell killing by target antigen engagement with engineered complementary intracellular antibody single domains fused to pro-caspase3Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:7d4b4421-a567-485c-b2c3-ede611dc0b8dEnglishSymplectic Elements at OxfordNature Research2019Chambers, JBrend, TRabbitts, T<p>Many tumour causing proteins, such as those expressed after chromosomal translocations or from point mutations, are intracellular and are not enzymes <em>per se</em> amenable to conventional drug targeting. We previously demonstrated an approach (<u>A</u>ntibody-antigen <u>I</u>nteraction <u>D</u>ependent <u>A</u>poptosis (AIDA)) whereby a single anti-β-galactosidase intracellular single chain Fv antibody fragment, fused to inactive procaspase-3, induced auto-activation of caspase-3 after binding to the tetrameric β-galactosidase protein. We now demonstrate that co-expressing an anti-RAS heavy chain single VH domain, that binds to mutant RAS several thousand times more strongly than to wild type RAS, with a complementary light chain VL domain, caused programmed cell death (PCD) in mutant RAS expressing cells when each variable region is fused to procaspase-3. The effect requires binding of both anti-RAS variable region fragments and is RAS-specific, producing a tri-molecular complex that auto-activates the caspase pathway leading to cell death. AIDA can be generally applicable for any target protein inside cells by involving appropriate pairs of antigen-specific intracellular antibodies.</p> |
| spellingShingle | Chambers, J Brend, T Rabbitts, T Cancer cell killing by target antigen engagement with engineered complementary intracellular antibody single domains fused to pro-caspase3 |
| title | Cancer cell killing by target antigen engagement with engineered complementary intracellular antibody single domains fused to pro-caspase3 |
| title_full | Cancer cell killing by target antigen engagement with engineered complementary intracellular antibody single domains fused to pro-caspase3 |
| title_fullStr | Cancer cell killing by target antigen engagement with engineered complementary intracellular antibody single domains fused to pro-caspase3 |
| title_full_unstemmed | Cancer cell killing by target antigen engagement with engineered complementary intracellular antibody single domains fused to pro-caspase3 |
| title_short | Cancer cell killing by target antigen engagement with engineered complementary intracellular antibody single domains fused to pro-caspase3 |
| title_sort | cancer cell killing by target antigen engagement with engineered complementary intracellular antibody single domains fused to pro caspase3 |
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