Stanford University Palo Alto, California, United States
Introduction:: Despite the curative potential of checkpoint blockade immunotherapy, a majority of patients remain unresponsive to existing treatments. Glyco-immune checkpoints – interactions of cell-surface glycans with lectin, or glycan binding, immunoreceptors – have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular platform for glyco-immune checkpoint blockade.
Materials and Methods:: AbLecs are bispecific antibody-like molecules comprising a tumor-targeting arm as well as a lectin “decoy receptor” domain that directly binds tumor glycans and blocks their ability to engage lectin receptors on immune cells. Western blot and mass spectrometry results indicated correct heterodimeric assembly of eight AbLec candidates, demonstrating the feasibility of the AbLec approach. We found that AbLecs bind cancer cell lines at nanomolar concentrations and block cognate Siglec receptor binding via flow cytometry.
Results, Conclusions, and Discussions:: AbLecs elicited tumor killing in vivo and in vitro via macrophage phagocytosis and NK cell and granulocyte cytotoxicity, matching or outperforming combinations of monospecific antibodies with lectin-blocking or glycan-disrupting therapies. Furthermore, AbLecs synergized with blockade of the “don’t eat me” signal CD47 for enhanced tumor killing. AbLecs can be readily designed to target numerous tumor-associated antigens and glyco-immune checkpoint ligands, and therefore represent a new modality for cancer immune therapy.