Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy
T-cell engaging (TCE) bispecific antibodies are potent drugs that trigger the immune system to eliminate cancer cells, but administration can be accompanied by toxic side effects that limit dosing. TCEs function by binding to cell surface receptors on T cells, frequently CD3, with one arm of the bis...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2373325 |
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| author | Amelia C. McCue Stephen J. Demarest Karen J. Froning Michael J. Hickey Stephen Antonysamy Brian Kuhlman |
| author_facet | Amelia C. McCue Stephen J. Demarest Karen J. Froning Michael J. Hickey Stephen Antonysamy Brian Kuhlman |
| author_sort | Amelia C. McCue |
| collection | DOAJ |
| description | T-cell engaging (TCE) bispecific antibodies are potent drugs that trigger the immune system to eliminate cancer cells, but administration can be accompanied by toxic side effects that limit dosing. TCEs function by binding to cell surface receptors on T cells, frequently CD3, with one arm of the bispecific antibody while the other arm binds to cell surface antigens on cancer cells. On-target, off-tumor toxicity can arise when the target antigen is also present on healthy cells. The toxicity of TCEs may be ameliorated through the use of pro-drug forms of the TCE, which are not fully functional until recruited to the tumor microenvironment. This can be accomplished by masking the anti-CD3 arm of the TCE with an autoinhibitory motif that is released by tumor-enriched proteases. Here, we solve the crystal structure of the antigen-binding fragment of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3 and use this information to engineer a masked form of the antibody that can activate by the tumor-enriched protease matrix metalloproteinase 2 (MMP-2). We demonstrate with binding experiments and in vitro T-cell activation and killing assays that our designed prodrug TCE is capable of tumor-selective T-cell activity that is dependent upon MMP-2. Furthermore, we demonstrate that a similar masking strategy can be used to create a pro-drug form of the frequently used anti-CD3 antibody SP34. This study showcases an approach to developing immune-modulating therapeutics that prioritizes safety and has the potential to advance cancer immunotherapy treatment strategies. |
| format | Article |
| id | doaj-art-34933b498de9441099c0a12d348a43a2 |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-34933b498de9441099c0a12d348a43a22025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2373325Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapyAmelia C. McCue0Stephen J. Demarest1Karen J. Froning2Michael J. Hickey3Stephen Antonysamy4Brian Kuhlman5Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USALilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, USALilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, USALilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, USALilly Biotechnology Center, Eli Lilly and Company, San Diego, CA, USADepartment of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USAT-cell engaging (TCE) bispecific antibodies are potent drugs that trigger the immune system to eliminate cancer cells, but administration can be accompanied by toxic side effects that limit dosing. TCEs function by binding to cell surface receptors on T cells, frequently CD3, with one arm of the bispecific antibody while the other arm binds to cell surface antigens on cancer cells. On-target, off-tumor toxicity can arise when the target antigen is also present on healthy cells. The toxicity of TCEs may be ameliorated through the use of pro-drug forms of the TCE, which are not fully functional until recruited to the tumor microenvironment. This can be accomplished by masking the anti-CD3 arm of the TCE with an autoinhibitory motif that is released by tumor-enriched proteases. Here, we solve the crystal structure of the antigen-binding fragment of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3 and use this information to engineer a masked form of the antibody that can activate by the tumor-enriched protease matrix metalloproteinase 2 (MMP-2). We demonstrate with binding experiments and in vitro T-cell activation and killing assays that our designed prodrug TCE is capable of tumor-selective T-cell activity that is dependent upon MMP-2. Furthermore, we demonstrate that a similar masking strategy can be used to create a pro-drug form of the frequently used anti-CD3 antibody SP34. This study showcases an approach to developing immune-modulating therapeutics that prioritizes safety and has the potential to advance cancer immunotherapy treatment strategies.https://www.tandfonline.com/doi/10.1080/19420862.2024.2373325Antibody engineeringbispecific antibodycancerCD3cytokine release syndromeHER2 |
| spellingShingle | Amelia C. McCue Stephen J. Demarest Karen J. Froning Michael J. Hickey Stephen Antonysamy Brian Kuhlman Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy mAbs Antibody engineering bispecific antibody cancer CD3 cytokine release syndrome HER2 |
| title | Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy |
| title_full | Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy |
| title_fullStr | Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy |
| title_full_unstemmed | Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy |
| title_short | Engineering a tumor-selective prodrug T-cell engager bispecific antibody for safer immunotherapy |
| title_sort | engineering a tumor selective prodrug t cell engager bispecific antibody for safer immunotherapy |
| topic | Antibody engineering bispecific antibody cancer CD3 cytokine release syndrome HER2 |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2373325 |
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