Abstract
This paper describes the synthesis, characterization, and functional activity of 26 MegaMolecule-based bispecific antibody mimics for T-cell redirection toward HER2+ cancer cells. The work reports functional bispecific MegaMolecules that bind both receptor targets, and recruit and activate T-cells resulting in lysis of the target tumor cells. Changing the orientation of linkage between Fabs against either HER2 or CD3ϵ results in an approximately 150-fold range in potency. Increasing scaffold valency from Fab dimers up to tetramers improves the potency of the antibody mimics up to 5-fold, but with diminishing returns in effective dose beyond trimeric formats. Antibody mimics that present either one or two Fabs against either receptor target allows for initial engagement of one cell type over the other. Finally, the antibody mimics significantly reduce HER2+ tumor volumes in a humanized xenograft model of breast cancer.
Original language | English (US) |
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Pages (from-to) | 26801-26807 |
Number of pages | 7 |
Journal | Journal of the American Chemical Society |
Volume | 146 |
Issue number | 39 |
DOIs | |
State | Published - Oct 2 2024 |
Funding
This work used the Flow Cytometry Core Facility and the Developmental Therapeutics Core at Northwestern University, which are supported by the Robert H. Lurie Comprehensive Cancer Center Support Grant (NCI CA060553). We thank N. Haack, E. Dempsey, G. Ma, and I. Stepien of the Developmental Therapeutics Core at Northwestern University for assistance with the mouse experiments. We thank B. Kimmel for their assistance with acquiring mass spectrometry data. All graphical representations of proteins and linkers were made with BioRender. The project depicted was sponsored by the Department of the Defense, Defense Threat Reduction Agency award HDTRA1-21-1-0038. The content of the information does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. The project was supported by the Robert H. Lurie Comprehensive Cancer Center - Liz & Eric Lefkofsky Innovation Research Award. The project was supported by the Pat & Shirley Ryan Family Research Acceleration Fund. This work used the Flow Cytometry Core Facility and the Developmental Therapeutics Core at Northwestern University, which are supported by the Robert H. Lurie Comprehensive Cancer Center Support Grant (NCI CA060553). We thank N. Haack, E. Dempsey, G. Ma, and I. Stepien of the Developmental Therapeutics Core at Northwestern University for assistance with the mouse experiments. We thank B. Kimmel for their assistance with acquiring mass spectrometry data. All graphical representations of proteins and linkers were made with BioRender. The project depicted was sponsored by the Department of the Defense, Defense Threat Reduction Agency award HDTRA1\u201321\u20131\u20130038. The content of the information does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. The project was supported by the Robert H. Lurie Comprehensive Cancer Center - Liz & Eric Lefkofsky Innovation Research Award. The project was supported by the Pat & Shirley Ryan Family Research Acceleration Fund.
ASJC Scopus subject areas
- Catalysis
- General Chemistry
- Biochemistry
- Colloid and Surface Chemistry