Antibody-lectin bispecifics for glyco-immune checkpoint blockade

Despite the curative potential of checkpoint blockade immunotherapy, most 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. AbLecs are bispecific antibody-like molecules comprising a cell-targeting antibody domain and a lectin “decoy receptor” domain that directly binds glycans and blocks their ability to engage inhibitory lectin receptors. AbLecs potentiate anticancer immune responses including phagocytosis and cytotoxicity, outperforming most existing therapies and combinations tested. By targeting a distinct axis of immunological regulation, AbLecs synergize with blockade of established immune checkpoints. AbLecs can be readily designed to target numerous tumor and immune cell subsets as well as glyco-immune checkpoints, and therefore represent a new modality for cancer immunotherapy.### Competing Interest StatementA patent application relating to antibody-decoy receptor chimeras has been filed by Stanford University (docket no. PCT/US2022/023166). Additionally, a patent for targeted cell surface editing mentioned in this work was filed by Stanford University (WO2018006034A1). J.C.S. and C.R.B. are co-founders of Valora Therapeutics. C.R.B. is a co-founder and scientific advisory board member of Firefly Bio, Lycia Therapeutics, Palleon Pharmaceuticals, Enable Bioscience, Redwood Biosciences (a subsidiary of Catalent), OliLux Bio, Grace Science LLC, and InterVenn Biosciences. All other authors have no conflicts of interest to declare.