Site-selective
acetylation of a single lysine residue
in a protein
that reaches a lysine acetyltransferase’s accuracy, precision,
and reliability is challenging. Here, we report a peptide-guided,
proximity-driven group transfer reaction that acetylates a single
lysine residue, Lys 248, of the fragment crystallizable region (Fc
region) in the heavy chain of the human Immunoglobulin G (IgG). An
Fc-interacting peptide bound with the Fc domain and positioned a phenolic
ester close to Lys 248, which induced a nucleophilic reaction and
resulted in the transfer of an acetyl group to Lys 248. The acetylation
reaction proceeded to a decent yield under the physiological condition
without the need for deglycosylation, unnatural amino acids, or catalysts.
Along with acetylation, functional moieties such as azide, alkyne,
fluorescent molecules, or biotin could also be site-selectively installed
on Lys 248, allowing IgG’s further derivatization. We then
synthesized an antibody–lipid conjugate and constructed antibody-conjugated
liposomes (immunoliposomes), targeting HER2-positive (HER2+) cancer
cells. We also built a bispecific antibody complex (bsAbC) covalently
linking an anti-HER2 antibody and an anti-CD3 antibody. The bsAbC
showed in vitro effector-cell-mediated cytotoxicity
at nanomolar concentrations. Compared with bispecific antibodies (bsAbs),
bsAbCs are constructed based on native IgGs and contain two antigen-binding
sites to each antigen, twice that of bsAbs. Altogether, this work
reports a method of site-selective acetylation of native antibodies,
highlights a facile way of site-selective IgG functionalization, and
underscores the potential of bsAbCs in cancer immunotherapy.
Immune modulation is a hallmark of cancer. Cancer–immune interaction shapes the course of disease progression at every step of tumorigenesis, including metastasis, of which circulating tumor cells (CTCs) are regarded as an indicator. These CTCs are a heterogeneous population of tumor cells that have disseminated from the tumor into circulation. They have been increasingly studied in recent years due to their importance in diagnosis, prognosis, and monitoring of treatment response. Ample evidence demonstrates that CTCs interact with immune cells in circulation, where they must evade immune surveillance or modulate immune response. The interaction between CTCs and the immune system is emerging as a critical point by which CTCs facilitate metastatic progression. Understanding the complex crosstalk between the two may provide a basis for devising new diagnostic and treatment strategies. In this review, we will discuss the current understanding of CTCs and the complex immune-CTC interactions. We also present novel options in clinical interventions, targeting the immune-CTC interfaces, and provide some suggestions on future research directions.
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