Covalent antibody recruiting molecules (cARMs) are synthetic chemical tools that direct
antibodies naturally present in human serum to tumor receptors leading to immune recognition
and elimination. cARMs have three general features: an antibody binding domain (ABD), an
antibody labelling domain (ALD), and a tumor binding domain. Proximal to the ABD, the ALD
contains an electrophilic group which is attacked by a nucleophilic amino acid residue on the
target antibody upon cARM binding. Previous cARMs use an acyl-imidazole (AL) ALD to
successfully covalently recruit anti-dinitrophenyl IgG validated via fluorescence SDS-PAGE,and
form immune complexes with PSMA+ HEK cells in ADCP flow experiments.1 Through MS
analysis, AL cARMs were demonstrated to target lysine-59 of antiDNP.1 Problematically, there
are several properties associated with AL chemistry that limit the therapeutic potential of
associated cARMs. These limitations include limited stability in vivo, single amino acid (lysine)
selectivity, and modest intramolecular protein labelling rates (10-5 s-1)1. To target novel antibody
residues and possibly improve the rate of antibody labelling, a second generation of cARMs has
been developed using sulfur fluoride exchange (SuFEx) chemistry as the ALD. Sulfur fluorides
have been broadly used in academic and industrial applications due to intrinsically high stability
and broad amino acid reactivity.2 SuFEx cARMs are hypothesized to have enhanced hydrolytic
stability compared to AL cARMs. This thesis explores the synthesis, stability, binding, and
labeling kinetics of SuFEx cARMs to advance cARM design and development for in vivo
applications. This research contributes collectively to the design and development of novel
therapeutics in chemical biology and immune-oncology research. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27851 |
| Date | 11 1900 |
| Creators | Eisinga, Sarah |
| Contributors | Rullo, Anthony, Chemical Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
Page generated in 0.0016 seconds