posted on 2020-03-13, 12:35authored byBenjamin Lake, Nickolas Serniuck, Eden Kapcan, Alex Wang, Anthony F. Rullo
Unprecedented
progress made in the treatment of cancer using the
body’s own immune system has encouraged the development of
synthetic molecule based immunotherapeutics. An emerging class of
these compounds, called Antibody Recruiting Molecules (ARMs) or Antibody
Engagers (AEs), functions by reversibly binding antibodies naturally
present in human serum and recruiting these to cancer cells. The recruited
antibodies then engage immune cells to form quaternary complexes that
drive cancer erradication. Despite their promise, the requirement
to form quaternary complexes governed by multiple equilibria complicates
an understanding of their in vivo efficacy. Particularly
problematic are low endogenous serum antibody concentrations and rapid
clearance of AEs from circulation. Here we describe a new class of
trifunctional chemical tools we call covalent immune recruiters (CIRs).
CIRs covalently label specific serum antibodies in a selective manner
with a target protein binding ligand. CIRs thereby exert well-defined
control over antibody recruitment and simplify quaternary complex
equilibium, enabling probing of the resultant effects on immune recognition.
We demonstrate CIRs can selectively covalently label anti-DNP IgG,
a natural human antibody, directly in human serum to drive efficient
immune cell recognition of targets. We expect CIRs will be useful
tools to probe how quaternary complex stability impacts the immune
recognition of cancer in vivo, revealing new design
principles to guide the development of future AEs.