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Engineering Tumor-Selective T Cell E...

McCue, Amelia,

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Engineering Tumor-Selective T Cell Engager Prodrugs for Cancer Immunotherapy /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Engineering Tumor-Selective T Cell Engager Prodrugs for Cancer Immunotherapy // Amelia McCue.
Author:	McCue, Amelia,
Description:	1 electronic resource (80 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-02, Section: B.
Contained By:	Dissertations Abstracts International86-02B.
Subject:	Biomedical engineering. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31483596
ISBN:	9798383687543

Engineering Tumor-Selective T Cell Engager Prodrugs for Cancer Immunotherapy /
McCue, Amelia,

Engineering Tumor-Selective T Cell Engager Prodrugs for Cancer Immunotherapy /Amelia McCue. - 1 electronic resource (80 pages)

Source: Dissertations Abstracts International, Volume: 86-02, Section: B.

The convergence of protein engineering and cancer immunotherapy in recent years has generated innovative therapeutics to treat disease by engaging a patient's own immune system to recognize and destroy cancer cells. T-cell engaging bispecific antibodies (TCEs) are potent drugs that trigger the immune system to eliminate cancer cells but 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 present on healthy cells. One strategy currently being tested to mitigate the toxicity of TCEs is to create pro-drug forms of the TCE that are not fully functional until recruited to the tumor microenvironment. Here, we solve the crystal structure of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3ε and use this information to engineer masked forms of the antibody that are removable in response to tumor-specific stimuli. We demonstrate with binding experiments and in vitro T cell activation and killing assays that a designed prodrug TCE (pro-TCE) that is activated by the tumor-enriched protease matrix metalloprotease 2 (MMP-2) 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 SP-34, expanding the masking strategy described here to multiple clinical anti-CD3 antibodies. This dissertation showcases an approach to developing T cell immune modulating therapeutics that prioritizes tumor-selective activity for enhanced safety that has the potential to advance cancer immunotherapy treatment strategies.

English

ISBN: 9798383687543Subjects--Topical Terms:

535387
Biomedical engineering.
Subjects--Index Terms:

Antibody engineering

Engineering Tumor-Selective T Cell Engager Prodrugs for Cancer Immunotherapy /
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502 $b Ph.D. $c The University of North Carolina at Chapel Hill $d 2024.
520 $a The convergence of protein engineering and cancer immunotherapy in recent years has generated innovative therapeutics to treat disease by engaging a patient's own immune system to recognize and destroy cancer cells. T-cell engaging bispecific antibodies (TCEs) are potent drugs that trigger the immune system to eliminate cancer cells but 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 present on healthy cells. One strategy currently being tested to mitigate the toxicity of TCEs is to create pro-drug forms of the TCE that are not fully functional until recruited to the tumor microenvironment. Here, we solve the crystal structure of a novel anti-CD3 antibody, E10, in complex with its epitope from CD3ε and use this information to engineer masked forms of the antibody that are removable in response to tumor-specific stimuli. We demonstrate with binding experiments and in vitro T cell activation and killing assays that a designed prodrug TCE (pro-TCE) that is activated by the tumor-enriched protease matrix metalloprotease 2 (MMP-2) 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 SP-34, expanding the masking strategy described here to multiple clinical anti-CD3 antibodies. This dissertation showcases an approach to developing T cell immune modulating therapeutics that prioritizes tumor-selective activity for enhanced safety that has the potential to advance cancer immunotherapy treatment strategies.
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650 4 $a Biochemistry. $3 518028
650 4 $a Biophysics. $3 518360
650 4 $a Immunology. $3 611031
653 $a Antibody engineering
653 $a Bispecific antibody
653 $a Cancer
653 $a Cytokine release syndrome
653 $a T cell activation
653 $a X-ray structure
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690 $a 0786
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710 2 $a The University of North Carolina at Chapel Hill. $b Biochemistry and Biophysics. $e degree granting institution. $3 3827175
720 1 $a Kuhlman, Brian $e degree supervisor.
773 0 $t Dissertations Abstracts International $g 86-02B.
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791 $a Ph.D.
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