Antibody-recruiting molecules (ARMs) are therapeutic tools that simultaneously
bind a hapten-specific serum antibody and a cancer cell surface protein, resulting in the
activation and recruitment of an immune cell to the cancer surface. However, ARM
efficacy is limited by the ability of ARMs to form a quaternary complex with the immune
cell receptor, antibody, and cancer cell surface. The Rullo lab has previously developed
and characterized a covalent ARM (cARM) that irreversibly links the ARM to the
antibody and simplifies the quaternary binding equilibria. cARMs have shown a marked
increase in both target immune recognition and therapeutic efficacy. However, cARM
efficacy is still limited by the affinity of the antibody for the immune receptor. We aim to
investigate how direct covalent engagement of the immune receptor and elimination the
antibody-immune receptor binding equilibria impacts immune activation and therapeutic
efficacy.
This thesis focuses on the chemical programming of macrophages through direct
covalent immune receptor engagement. We have developed and characterized covalent
immune programmers (CIPs), which are molecules that contain a macrophage targeting
domain and a tumour targeting domain. The macrophage targeting domain binds the
activating receptor CD64 on the macrophage surface and contains a chemical warhead
that covalently labels the receptor once bound. The tumour targeting domain can
promote macrophage tumour engagement resulting in tumoricidal function. Flow
cytometry experiments have shown that CIPS are able to bind Fc receptors specifically
and effectively on the surface of macrophages. Further, CIPs were able to induce
macrophage activation and induce target specific phagocytosis. These experiments
have also shown that direct engagement of the receptor by the CIP is more effective
than antibody-mediated engagement, suggesting that overall immune complex stability
affects immune cell activation. Taken together, these concepts can be used to guide
future immunotherapeutic design. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/29115 |
| Date | 11 1900 |
| Creators | Yang, Zi Ling (Sissi) |
| Contributors | Rullo, Anthony, Chemistry and Chemical Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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