Macrophages and desmoplastic reactions are associated with resistance to current immuno-oncology therapies. We identified a subset of macrophages that expanded during fibrotic, non-oncologic diseases in multiple organs in both patients and murine models. These macrophages were found near activated fibroblasts on the fibrotic margins. Leveraging human cells and murine models we uncovered cytokines that drive phenotypic and functional aspects of these scar-associated macrophages. Using mutli-omics approaches, we determined that similar macrophages are enriched in several murine tumor models and human tumors where they appear to be associated with poor survival outcomes.

Innate and therapy-induced resistance to checkpoint inhibitors limit the response rate in many cancers. An increased TGF-ß signature is linked to poor clinical outcomes and checkpoint resistance. avß8 controls localized and cell-type-specific activation of TGF-ß 1 and 3 to negatively regulate immunity and promotes tolerance. Selective avß8 inhibition is a safe and efficient approach to reverse TGF-ß-driven immunosuppression, improving anti-tumor adaptive immune responses and immune infiltration into the TME.

RAPID is a next-generation chemoproteomics technology for discovering small molecules that bind to any target of interest inside of a living cell. Using RAPID, we have discovered the first described ligands for the transcription factor IRF3, which drives the interferon response downstream of STING. We will also describe the discovery of an orphan transporter that is required for the uptake of paracrine 2’,3’-cGAMP into primary macrophages.

Cancer cells consume large amount of glucose releasing lactate, the final product of glucose metabolism, to the tumor microenvironment (TME) via membrane-bound monocarboxylate transporters (MCT1 and MCT4). Lactate-rich tumors block anti-tumor immunity and create an immunosuppressive TME thus allowing rapid tumor growth. We have discovered a series of small molecule dual inhibitors of MCT1/4 which act via multiple mechanisms, intrinsic cell killing, and activation of local anti-tumor immunity, leading to tumor growth reduction in multiple mouse tumor models. This could be a novel therapeutic modality to address deficiencies of current cancer treatments including immune checkpoint inhibitors.

SUMOylation is a post-translational modification that regulates protein function and requires activation of SUMO protein by SUMO Activating Enzyme (SAE). Here we describe the identification of subasumstat (TAK-981), a mechanism-based inhibitor of SAE, which forms a SUMO-TAK-981 adduct. Treatment with TAK-981 in murine models was shown to activate multiple immune cells through induction of a type I interferon response to promote anti-tumor immunity. Subasumstat is currently under clinical evaluation.

PTPN2/N1, negative regulators of immune activation pathways, emerged as hits in an in vivo CRISPR screen to identify tumor-intrinsic targets that enhance sensitivity and overcome resistance to anti-PD-1 treatment. Here we report the discovery of a first-in-class PTPN2/N1 inhibitor, a promising novel immunotherapy that both increases tumor sensitivity to immune-mediated killing and enhances the function of multiple immune cell subsets. ABBV-CLS-484 is currently being evaluated in Phase I clinical trials.

Casitas B-lineage lymphoma b (CBL-B) is an E3 ligase that functions as a negative regulator of T, NK, and myeloid cells. Mice deficient in CBL-B reject tumors in syngeneic models, suggesting that inhibition of CBL-B may be a novel therapeutic strategy. We present discovery and optimization of compounds including NRX-8 (KD=20nM) that glue CBL-B into an inactive conformation. NRX-8 increases T cell activation in response to TCR stimulation and inhibits tumor growth in syngeneic models of cancer when dosed orally. We present preclinical data on NX-1607, a more potent CBL-B inhibitor being evaluated in a Phase I trial in multiple oncology indications.

Formation of ternary complexes between a ligase, a molecular glue, and a disease-modulating protein is the first step in a sequence of events leading to protein degradation.  In this presentation, we discuss the SPR and X-ray crystallographic characterization of ternary complexes involving a molecular glue that binds to the ligase Cereblon and induces the binding of the zinc finger-containing transcription factor IKZF2.

The presence of extracellular adenosine is frequently responsible for the creation of an immunosuppressed tumor microenvironment through activation of the A2a and A2b receptors expressed on intratumoral immune cells. AB928 (etrumadenant) is a novel, selective, and non-brain penetrant small molecule dual A2aR/A2bR antagonist designed to potently block the immunosuppressive effects of high concentrations of adenosine in the tumor microenvironment. This presentation discusses the design, characterization, and SAR of a series of potent A2aR/A2bR antagonists culminating in the discovery of etrumadenant.

Due to its role in immune cell trafficking, CCR2 is pursued as a target in autoimmunity and immuno-oncology. This pursuit, however, has not yet yielded any clinical candidates. Failures have been attributed to complexities of CCR2 biology and suboptimal properties of the therapeutic candidates. I will present an overview of CCR2-targeting modalities, discuss the structural principles of their affinity and selectivity, and share recent findings about unexpected side-effects of CCR2 inhibition.

High levels of Treg infiltration in the tumor microenvironment (TME) lead to a poor prognosis in patients. The chemokine receptor CCR4 is highly expressed on Treg where it functions to attract them into the TME where they inhibit immune response. To reduce the prevalence of Treg in the TME we have discovered and developed FLX475 a potent, selective, and orally available CCR4 antagonist.