Our Research & Initiatives

       The research in our laboratory integrates synthetic chemistry with glycobiology to explore the cellular and molecular mechanisms that control immune responses toward cancer and human pathogens. Our focus is to develop chemical tools to study these processes and translate our findings into new therapeutic approaches.

       Our early work was focused on the development of chemical tools to explore the relevance of protein glycosylation in human disease. The glycome, defined as the full complement of glycans that a cell produces, is involved in a myriad of physiological processes, including angiogenesis, fertilization, stem cell development, and neuronal development. Changes in the glycome have also been shown to mark the onset of cancer and inflammation. Produced by the secondary metabolism rather than encoded in the genome, glycans are assembled in a stepwise fashion by multiple enzymes and thus by multiple genes.         Consequently, genetic and biochemical tools alone cannot be used to define all aspects of the glycome. Therefore, my lab chooses to develop complementary chemical tools that can be applied in parallel to assemble a picture of the glycome both from the “bottom up” and from the “top down”. Early chemical tools developed by my lab include:

• Biocompatible copper catalysts for Cu(I)-catalyzed azide-alkyne cycloaddition that enabled fast, selective click reactions for labeling glycans, lipids, and proteins in living systems, which have been used by more than 200 labs worldwide.

• Chemoenzymatic methods for the detection and modification of cell-surface glycans.

       Not only have these tools opened new avenues for imaging biomolecules in living animals, but they have also facilitated the discovery of new biomarkers for diseases and the development of new modalities with potential therapeutic values. Major discoveries and technique development enabled by these tools include:

• Discovery of fucosylated glycans as alternative influenza virus receptors, expanding the known host–virus interaction mediators beyond sialylated glycans.

• Demonstration that mutation of the cloche gene reduces fucosylation during zebrafish embryogenesis—defects partially rescued by fucose or GDP-fucose supplementation.

• Identification of a 13-fold decrease in N-acetyllactosamine (LacNAc) expression in early-stage lung adenocarcinoma, suggesting its potential as an early diagnostic biomarker.

• Invention of the first cell-based glycan arrays through chemical display of defined oligosaccharides on living cells, enabling direct screening of glycan-protein interactions for drug discovery.

 

       In these studies, we found that H. pylori α1-3-fucosyltransferase has an unexpectedly broad donor substrate scope—it can transfer large biomolecules, including full-length antibodies, to glycan acceptors on live-cell glycocalyces when the antibody is conjugated to the donor substrate GDP-fucose. This rapid and versatile approach provides a powerful complement to genetic engineering for generating antibody–cell conjugates (ACCs) for adoptive cell therapy. These ACCs exhibited robust antitumor activity ex vivo and in vivo in mouse tumor models. We are now extending this strategy to create a T-cell–cytokine conjugate library aimed at overcoming cytokine instability and systemic toxicity, thereby producing “armored” T cells for adoptive therapy.

       From the above studies, we found ourselves in a unique position to contribute new tools that would propel the study of oncology and immunobiology, and this has been the theme of my group at Scripps for the past ten years. We are developing tools to explore the cellular and molecular mechanisms that control immune responses toward cancer and other human diseases with a focus on the following unsolved problems in immunoncology and pharmacology:

• What are the compositions and properties of tumor-specific antigen (TSA)-reactive and bystander tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment?

• How to address the on-target, off-tumor toxicity of chimeric antigen receptor (CAR)-T cells?

• Can we enhance effector function and longevity of T cells for treating chronic infection and cancer?

• How to direct adoptively transferred immune cells home specifically to diseased tissues?

• How to overcome the immunosuppressive tumor microenvironment to treat solid tumors?

 

Highlights of our major technological innovations over the past five years include:

• FucoID, the first genetic engineering–free approach for isolating the entire repertoire of tumor-specific T cells from solid tumors, paving the way for scalable and cost-effective personalized immunotherapy.

• Bispecific T-cell engager (BiTE)–sialidase fusion proteins, designed to overcome the limited efficacy of conventional BiTE molecules in solid tumors.

• A first-in-class dual-targeting degrader, capable of simultaneously eliminating two glycoimmune checkpoint receptors to overcome resistance to anti-PD-1 and anti-CTLA-4 therapies.