Researchers from MIT and Stanford University have developed multifunctional molecules called AbLecs to block sugar-based immune checkpoints on cancer cells. This approach aims to enhance immunotherapy by allowing immune cells to better target tumors. Early tests in cells and mice show promising results in boosting anti-tumor responses.
A team led by Jessica Stark at MIT, with senior author Carolyn Bertozzi at Stanford, has introduced AbLecs, which combine antibodies with lectins to target glycans on cancer cells. These glycans, often featuring sialic acid, bind to Siglec receptors on immune cells, mimicking the PD-1/PD-L1 pathway to suppress attacks on tumors.
The innovation addresses limitations in existing checkpoint inhibitors, which work for some patients but fail for many. By using antibodies like trastuzumab, which targets HER2 in breast, stomach, and colorectal cancers, the AbLecs deliver lectins such as Siglec-7 or Siglec-9 directly to tumor surfaces. This blocks sialic acid interactions, activating immune cells including macrophages and natural killer cells.
In laboratory experiments, AbLecs prompted immune cells to kill cancer cells more effectively. Mouse studies, using models with human Siglec and antibody receptors, demonstrated reduced lung metastases compared to trastuzumab alone after injecting cancer cells.
The design's modularity allows swapping components: antibodies like rituximab for CD20 or cetuximab for EGFR, or different lectins for other glycans, even integrating PD-1 targets. "AbLecs are really plug-and-play. They're modular," Stark noted, highlighting adaptability for various cancers.
Stark, an Underwood-Prescott Career Development Professor in biological and chemical engineering at MIT and a Koch Institute member, emphasized the potential: "We created a new kind of protein therapeutic that can block glycan-based immune checkpoints and boost anti-cancer immune responses."
The findings appear in Nature Biotechnology. The researchers have founded Valora Therapeutics to advance AbLecs toward clinical trials within two to three years.
