Major research interests

We focus on developing emerging technologies to address unmet needs in antibody discovery for multi-transmembrane proteins (including GPCRs and ion channels), B-cell based gene therapy for lysosomal storage diseases and hemophilia, novel T-cell engagers (BiTEs) redirecting T-cell immunity against cancer, and antibody-based targeted protein degradation. We are also dedicated to deciphering the functional mechanisms of tumor tertiary lymphoid structures (TLS) in immunotherapy to develop next-generation therapies, leveraging clinical collaborations. Overall, our primary research centers on B-cell biology, encompassing antibody discovery, B-cell engineering, and their clinical applications.

1) Antibody pipeline

B-cell plays a major role in adaptive immunity, contributing to antibody production, antigen presentation, and cytokine production in response to pathogen challenges. Monoclonal antibody (mAb) produced from single B-cell significantly advances both basic research and clinical applications. Despite the development of multiple antibody discovery pipelines such as hybridoma technology, single B-cell cloning, and various antibody surface display technologies, there remains an unmet need for the discovery of antibodies targeting multi-transmembrane proteins. This challenge stems from the difficulties associated with purifying these complex proteins. Moreover, GPCRs, ion channels, and transporters are recognized as potential drug targets, with approximately 34% of approved drugs targeting GPCRs. However, no antibody-based drug targeting ion channel has been developed and only two GPCR targeting mAbs are approved because of the challenges in the isolation of antibodies targeting these multi-transmembrane proteins. We hypothesize that displaying multi-transmembrane proteins (such as GPCRs and ion channels) on the cell surface can serve as effective antigens and probes for isolating specific monoclonal antibodies (mAbs). This approach offers an alternative strategy capable of overcoming the challenges associated with conventional methods for mAb discovery against these difficult targets. In addition, because of the conformational characteristics of nanobodies, like small size and long CDR3, they are able to target cryptic epitopes and membrane proximal epitopes for these difficult multi-transmembrane proteins. Here, we further successfully created a fully human nanobody scaffold by structure alignment and logical mutation screening. Furthermore, we designed a synthetic nanobody library (phage and yeast display) carrying with similar frequency of amino acids in CDR1, 2 and 3 regions to those from human antibody, thus allowing us to directly isolate fully human nanobody targeting these multi-transmembrane proteins. We will leverage this pipeline to develop membrane-targeting nanobodies that address unmet clinical needs.

2) Protein engineering

Immunotherapy has revolutionized cancer treatment by fundamentally shifting the therapeutic paradigm from directly attacking tumors to empowering the patient's own immune system against cancer. Despite its transformative potential, immunotherapy faces significant challenges that limit its broad clinical application. (1) Variable Response Rates – many patients (particularly with cold tumors lacking T-cell infiltration) show primary resistance, often due to immunosuppressive tumor microenvironments (TME), low tumor mutational burden, or deficient antigen presentation; (2) Acquired Resistance – initially responsive tumors may evade therapy via antigen loss, upregulation of alternative checkpoints (e.g., TIM-3, LAG-3), or T-cell exhaustion; (3) Delivery Limitations – solid tumors pose physical barriers (fibrosis, abnormal vasculature) that impede drug/T-cell penetration; (5) Biomarker Gaps – while PD-L1 expression and TMB offer some guidance, robust predictive biomarkers remain elusive. We will leverage our integrated strengths—the nanobody pipeline for deep tissue penetration, engineered BiTEs for precise T-cell redirection, and the targeted protein degradation platform—to specifically address key immunotherapy challenges.

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