NGM Biopharmaceuticals, Inc. disclosed its fourth oncology development candidate, NGM831, an antagonist antibody designed to block the interaction of ILT3 with fibronectin, as well as with other ligands. The announcement coincides with a publication in Cancer Immunology Research, a journal of the American Association for Cancer Research, describing NGM’s discovery of ILT3’s functional ligand, fibronectin, an extracellular matrix protein that forms a fibrillar network within the tumor stroma. This discovery enabled the development of NGM831, which joins NGM’s growing portfolio of wholly owned oncology antibody programs, including NGM120 (anti-GFRAL), NGM707 (anti-ILT2/ILT4) and NGM438 (anti-LAIR1). Myeloid cells often represent the most abundant tumor-associated immune cells and, in some tumors, myeloid cells alone account for more than half of the tumor mass. Through systematic screening, NGM was able to identify the suppressive receptors that are most highly enriched in myeloid cells, including four members of the LILR family: ILT2, ILT3, ILT4 and LAIR1. These receptors may play a central role in establishing the immune suppressive state of the tumor microenvironment. NGM plans to initiate first-in-human testing of NGM831 in the first half of 2022. In July 2021, NGM announced the initiation of a Phase 1/2 study of NGM707 when given alone or in combination with KEYTRUDA® (pembrolizumab) in patients with advanced solid tumors, which is anticipated to enroll 180 patients. NGM also plans to initiate a Phase 1 study of NGM438 in advanced solid tumors in the first half of 2022. As detailed in the publication, ILT3 is a fibronectin-binding inhibitory immune receptor that receives signals from the extracellular matrix to directly promote myeloid cell suppression. ILT3 is expressed specifically on tumor-associated myeloid cells, with particularly high expression on tolerogenic dendritic cells (DCs), myeloid-derived suppressor cells and M2 macrophages. This receptor is upregulated in several tumor types and is associated with poor survival7,8. Moreover, fibronectin has been shown to be upregulated in multiple cancers and associated with tumor progression9,10. For tumors in which both ILT3 and fibronectin are upregulated, the ILT3-fibronectin pathway may act as a stromal checkpoint to repress myeloid cell function. Designed to inhibit ILT3 interactions with fibronectin and other ligands, NGM831 is expected to reprogram tolerogenic DCs into stimulatory cells with enhanced Fc receptor activity as well as to enhance T cell infiltration and activation. The findings published are the latest research underpinning NGM’s growing oncology portfolio focused on tumor stroma biology and myeloid reprogramming to enhance antitumor immunity.