Jessica C. Stark, Melissa A. Gray, Itziar Ibarlucea-Benitez, Marta Lustig, Annalise Bond, B. Cho, Ishika Govil, T Luu, Megan Priestley, Tim S. Veth, Wesley J. Errington, Bence Bruncsics, Mikaela K. Ribi, L W Williams, Casim A. Sarkar, Simon Wisnovsky, Nicholas M. Riley, Meghan A. Morrissey, Thomas Valerius, Jeffrey V. Ravetch, Carolyn R. Bertozzi
Despite the curative potential of checkpoint blockade immunotherapy, many patients remain unresponsive to existing treatments. Glyco-immune checkpoints, which involve 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 system 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 cancer cell destruction by primary human immune cells in vitro and reduce tumour burden in a humanized, immunocompetent mouse model, 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 tumours and immune cell subsets as well as glyco-immune checkpoints, thus representing a potential modality for cancer immunotherapy.