Macrophages adopt functional roles in response to signals from the environment. Tumor-associated macrophages (TAMs) are regulators of interactions between immune system and cancer, fuel tumor progression, impact responses to therapy. We found novel targets changing human macrophages into anti-tumor response enablers. Verseau lead programs targeting PSGL-1 and VSIG4 reprogram macrophages via different molecular pathways to a pro-inflammatory state, activate T cells, and attract naive immune cells to generate anti-tumor responses.

With the phenomenal success of antibodies targeting PD-1/PD-L1, immunotherapy has become a mainstay in cancer therapy. While approved checkpoint antibodies primarily activate T cells, those targeting CD47-SIRPa axis that impact macrophages are showing a lot of promise. Small molecule-based therapeutics targeting CD47 offer several advantages including selectively inducing phagocytosis of tumor cells, which could be challenging with Fc-containing antibodies or fusion proteins. Our efforts in developing small molecule orally bioavailable CD47 antagonists will be summarized in this presentation.

The tumor microenvironment contains high levels of suppressive myeloid cells that may contribute to innate checkpoint inhibitor resistance. Pionyr’s Myeloid Tuningä approach involves altering the composition and/or the function of myeloid cells in the TME. Pionyr developed an anti-TREM2 monoclonal antibody termed PY314 that is being tested in the clinic. I present our efforts to understanding the MOA of PY314 and profiling TREM2 expression in human tumors.

The CBL-B E3 ubiquitin ligase functions as a negative regulator of T cell receptor activation. We report discovery of NX-1607, an orally bioavailable CBL-B inhibitor that demonstrates anti-tumor activity in multiple preclinical tumor models. NX-1607 triggers rapid NK and T cell infiltration of tumors and shows increased frequency of tumor rejection in combination with anti-PD-1. Our studies provide rationale for clinical development of NX-1607 in advanced malignancies.

Homozygous p16/CDKN2a deletions that also involve co-deletion of the adjacent gene encoding methylthioadenosine phosphorylase (MTAP) are prevalent in ~10% of all human cancers. The absence of MTAP leads to accumulation of its substrate methylthioadenosine (MTA), creating an environment unique for cancerous cells. Here we describe MRTX9768, an inhibitor of Protein Arginine N-Methyl Transferase (PRMT5)/MTA complex that provides an opportunity to block PRMT5 in cancer cells while sparing wildtype cells.

We identified modifications of specific proteins that exclusively arrest mitosis in human malignant cells by inserting flaws in their mitotic spindles. Cancer cells are efficiently eradicated by Mitotic catastrophe cell death, while similarly treated healthy cells are spared and continue to proliferate as untreated cells. We identified molecules causing the specific modifications. This cytotoxic effect was examined in a variety of human resistant cancer cells and in xenografts.    

Sino Biological is a global leader in the development and manufacture of high-quality, ISO9001-certified bioreagents including recombinant proteins, antibodies, cDNA clones and assay kits. The company has one of the world’s largest selections of bioactive recombinant proteins and a comprehensive CRO services offering. An overview of the company’s product and service portfolios as it pertains to the detection of biomarkers related to immuno-oncology along with related case studies will be given.

Integrin αvβ8 mediated cell type-specific and tissue localized activation of TGFβ1/3 to regulate the immune system. Orally administrated αvβ8 targeted inhibitor is a potent modulator of anti-tumor immune responses acting across the immunologic synapse to enhance CD8 T cells responses, activate Dendritic Cells, and reduce Tregs functionality in syngeneic mouse tumor models. αvβ8 antagonism is a promising therapeutic approach to ICB refractory tumors.

I present our recently published data on the structure and dynamics of the full length CD47, a membrane protein receptor against which many biopharma companies are developing 'blockers' for potential use as an IO therapy. The structure reveals that this receptor adopts a novel transmembrane domain fold and highlights the important role of the extracellular loops for immune recognition, signaling and therapeutics. [Nat Commun 12, 5218 (Sep2021)]

Surface Plasmon Resonance (SPR) is a label-free technique widely used to study interactions between biomolecules.  However, due to challenges with purifying membrane proteins, it is very difficult to obtain binding affinity and kinetics data with SPR.  SPR microscopy (SPRM) is a new technology capable of measuring binding interactions on cell membranes.   Basic principles of SPRM and various membrane protein binding examples will be presented in the talk.

Resolution of inflammation is elicited by proresolving lipids, which activate GPCRs such as ChemR23. ChemR23 is overexpressed in inflamed colon tissues of severe IBD patients unresponsive to anti-TNF and associated with mucosal neutrophil accumulation. Agonist anti-ChemR23 antibody induces receptor signaling, and reduces neutrophil apoptosis at the site of inflammation. In vivo, agonist anti-ChemR23 triggers resolution of ongoing chronic colitis models, decrease tissue lesions, fibrosis and inflammation-driven tumors.

BXQ-350 is a first-in-class and first-in-human nanovesicle formulation of Saposin C, a lysosomal activator protein involved in sphingolipid metabolism and de novo biosynthesis of ceramides, that targets phosphatidylserine. Expression of phosphatidylserine has been recognized as a global immunosuppressive signal and ceramides are important cell signaling and immune-stimulating molecules. BXQ-350’s safety profile and unique dual MOA were investigated in Phase 1 studies in cancer patients; results demonstrated that BXQ-350 was safe and well-tolerated and had evidence of single agent activity. Data will be presented in support of the immune involvement of these novel targets across diseases.

The SARS-CoV-2 main protease MPro has been a focus of novel therapeutic development. Through an open-science approach, the COVID Moonshot initiative discovered potent inhibitors of the SARS-CoV-2 MPro by combining crowdsourcing, high-throughput experiments and machine learning. All data generated are fully open to other researchers. The Moonshot initiative partnered with Drugs for Neglected Disease initiative (DNDi) to develop lead compounds into oral antivirals for rapid and equitable downstream access.

COVID-19 requires therapeutic interventions that can be rapidly identified and translated to clinical care. Drug repurposing can significantly accelerate translation that can be directly tested in Phase-II clinical studies and serve as starting points for de novo drug development. Using high content screening for FDA-approved drugs to identify SARS-CoV-2 antivirals, we identified 17 potent hits and are using them for viral target ID and the development of novel replication complex inhibitors.

We developed the strategy of the substrate envelope as an explicit method to avoid drug resistance and develop robust inhibitors. With an experimental dataset of viral proteases, we integrate alterations in protein sequence and inhibitor with changes in potency.  We map this data to our crystallographic structures and parallel molecular dynamics with machine learning to elucidate the molecular mechanisms and avoid drug resistance.