In recent years, several small molecule strategies have been used to harness the natural defences of the immune system. One successful strategy involves the design of antibody engagers (AEs), which redirect hapten specific antibodies to target tumor receptors. In this approach, immune recognition is regulated by the reversible formation of a quaternary complex between the antibody (Ab), tumor receptor, and two binding domains of the AE. To further investigate the kinetics of immune recognition and improve upon the multicomponent AE strategy, the Rullo lab has developed dual-binding compounds known as covalent antibody recruiting molecules (cARMs). Through covalent immune recognition (CIR), these molecules bind and covalently link to natural dinitrophenyl (DNP) antibodies to form covalent complexes [CIR-Ab]. DNP antibodies are covalently modified through the antibody-labelling domain (ALD) of the cARM, subsequently directing the CIR-Ab complex to the target tumor receptor. Recent work in the Rullo group has demonstrated PSMA-specific CIRs successfully linked to lysine-56 of anti-DNP immunoglobin G in human serum. Designed to contain lysine selective acyl-imidazole ALDs, these CIRs had modest hydrolytic stability ranging from 9 to 12 hours in vitro. To expand the scope of CIR technology to other antibody binding sites and improve their stability in vitro and potentially in vivo, new CIRs will be equipped with sulfur fluoride and triazole exchange (SuFEx/SuTEx) ALD chemistries. Since its development in 2014, SuFEx has been used in a variety of biological applications for covalent labelling of lysine, tyrosine, serine and histidine. Sulfonyl fluorides are also known to highly resistant against hydrolysis in acidic, basic, and harsh conditions, making them excellent candidates for CIR technology. This work will summarize the synthesis and preliminary testing of sulfonyl CIRs. The development of sulfonyl CIRs will provide more rapid and selective chemical tools that can directly interrogate immune recognition in vivo.

Chemically tuning covalent antibody recruiting molecules to modulate target immune recognition and response: Applications of sulfonyl fluoride click chemistry

ACS Spring Meeting 2021

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