Assistant Professor of Biological Engineering Massachusetts Institute of Technology Cambridge, Massachusetts, United States
Disclosure(s):
Jessica Stark, PhD: No relevant disclosure to display
Introduction/Rationale: 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.
Methods: Here, we describe antibody-lectin chimeras (AbLecs), a modular platform for glyco-immune checkpoint blockade. 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.
Results: We demonstrate proof-of-concept for the AbLec platform through the development and characterization of AbLecs combining tumor-targeting antibodies with decoy receptor domains from Siglecs-7 and -9, which have been shown to mediate immune suppression in multiple cancers. We show that tumor-targeting AbLecs enhance antibody-dependent phagocytosis and cytotoxicity of cancer cells in vitro and reduced tumor burden in vivo compared to the parent monoclonal antibody. We demonstrate that the AbLec platform can be applied to target diverse tumor-associated antigens, and cancer cells with varying levels of antigen expression. Further, we designed and validated dual blockade AbLecs that simultaneously block protein-based immune checkpoints (e.g., PD-1/PD-L1, CD47/SIRPα) as well as glyco-immune checkpoints that restrain productive anticancer immune responses (e.g., Siglec-7, galectin-9). We found that glyco-immune checkpoint blockade was synergistic with blockade of these established checkpoints.
Conclusion: Our results indicate that AbLecs target a non-redundant axis of immune suppression in cancer and could expand the subset of patients who respond to immunotherapy. In sum, AbLecs represent a generalizable approach for glyco-immune checkpoint blockade and a new modality for cancer immunotherapy.
