Tzu-Hsuan (Leon) Huang

Lead a multidisciplinary immunology discovery organization of 20 scientists (including 10 PhD-level scientists) focused on small-molecule therapeutics for autoimmune disease and immuno-oncology • Drive discovery programs against historically “undruggable” targets by leveraging Vividion’s proprietary chemoproteomics and small-molecule platform to enable novel target identification and druggability assessment. • Partner with executive and functional leadership to shape platform and portfolio strategy, spanning target identification and validation, screening, hit identification, hit-to-lead, and lead optimization across multiple autoimmune indications including vitiligo, SLE, IBD, alopecia areata, hidradenitis suppurativa, and fibrosis. • Provide scientific and strategic leadership for portfolio programs advancing toward IND-enabling studies and Phase 1 clinical trials. Provide insight in translational biomarker strategies, ensuring alignment with program objectives and clinical development plans throughout the process. • Supervise immunology program leads and serve as a key interface with cross-functional teams (chemistry, pharmacology, translational science, and development) to ensure alignment on program strategy, timelines, and deliverables. • Support and guide CRISPR base-editing screening initiatives to identify novel, druggable sites on targets relevant to autoimmune disease and immuno-oncology. • Mentor and develop scientific leaders within the organization, fostering technical excellence, strategic thinking, and career progression across the group.

• The primary aim of my research is to understand the mechanisms in potentiating anti-tumor immune responses, and I am currently focused on the following areas: (1) Identify novel immuno-oncology targets with data mining in bioinformatics and develop innovative therapeutics in targeting immune suppressor, stromal and tumor cells in the tumor microenvironment. (2) Develop antibody cytokine fusions for controlled delivery of immune modulatory cytokines for T cell and NK cell anti-tumor immune responses. • One publication in major peer-reviewed journal.

Supervised a team of 21 scientists with 9 PhDs conducting target validation and delivering IND-enabling packages of IO therapeutics (biologics and small molecules) • Developed an engineered IL15 cytokine mutein fused to an anti-PD-1 that improves intra-tumoral T-Cell function and anti-tumor immunity (Phase 1 studies with advanced or metastatic solid tumors, NCT04628780). • Supported multiple clinical IO programs for biomarkers and combinational strategies. 1.PD1-IL15 (Phase 1, CRC and NSCLC). 2.PD-L1 x CD47 bi-specific (Phase 1, NSCLC and head & neck). 3. Maplirpacept (SIRPα-Fc, Phase 1/2 in hematological cancer indications). • Collaborated with in vivo pharmacology, protein engineering, medicinal chemistry, CompBio and clinical development groups to pursue the most promising IO drug candidates through clinical trials. • Developed strategies in applying ADC technology for targeted delivery of small molecule modulators of tumor immunogenicity via antibody. • Contributed to overall strategy for cancer immunology and implement innovative strategies for immune engagers (NK cells and myeloid cells) and effectively modulating cytokine functions (IL-15, IL-12, IL-18, and IFNa) to elicit T and NK cell anti-tumor immunity (PD-1 targeted IL-15 advanced to Phase 1, PD-1 targeted IL-12 achieved IND filing). • Contributed to the overall strategy for tumor immunogenicity and immune evasion biology, i.e., neoantigen generation, deubiquitinating enzymes (DUBs), epigenetic disruption of tumor defense mechanisms, and role of innate immune cells in tumor recognition. • Discovered and developed new therapeutic modalities (mRNA-LNPs) for cancer immunotherapy focusing on tumor intrinsic targets and mechanisms. • Led collaborations on novel IO targets with internal and external partners (CROs, academic and research institutes). • Contributed to several preclinical/clinical projects resulting in four publications in major peer-reviewed journals (one co-corresponding authored publication).

Supervised and mentored a team (5 FTEs including PhD and non-PhD scientists) to develop next-generation cancer immunotherapy and identify/validate novel ADC targets, warheads and MOAs for solid tumors (prostate, CRC, and NSCLC). • Innovated antibody cytokine fusions in potentiating anti-tumor immune responses in anti-PD1/PD-L1 refractory tumors. (anti-PD-L1 and IFN-α fusion antibody published at 2018 AACR annual conference and PLOS One). • Identified novel ADC and IO targets with data mining in bioinformatics and developed innovative therapeutics in targeting immune suppressor, stromal, and tumor cells in the tumor microenvironment. • Scientific liaison for Abbvie and academic research collaborations. • Established CRISPR screening platform in primary T cells and identified novel targets for IO therapeutics. • Developed NAMPT inhibitor antibody-drug conjugates for castration-resistant prostate cancer (CRPC). • Coordinated multidisciplinary teams to generate lead immuno-oncology therapeutic for clinical development. • Served as Corresponding Author for two publications in major peer-reviewed journals.

Supervised and mentored non-PhD scientists to developed novel anti-cancer therapeutics using monoclonal and bispecific antibody platforms. • Profiled infiltrating immune cells and tumor cells in the tumor microenvironment and identify novel targets for cancer immunotherapy. • Investigated the mechanism of Apo2L/TRAIL and the death receptor 5 agonist antibody AMG 655 cooperation in promoting receptor clustering and anti-tumor activity, leading to a manuscript published in Cancer Cell.

Postdoctoral scholar in Dr. Mien-Chie Hung’s laboratory. Led projects to investigate novel signaling cascades initiated by EGFR and their potential roles in human cancer development. • First authored publication in Cancer Cell -demonstrated that EGFR enhances p56Lyn activity through Y32 phosphorylation, which potentiates the downstream MCM7 Y600 phosphorylation and positively modulates minichromosome maintenance complex assembly and cancer cell proliferation. The identified tyrosine phosphorylation cascade, namely EGFR - phospho-p56Lyn Y32 - phospho-MCM7 Y600, links EGFR and Lyn in MCM7-mediated DNA replication licensing, which is a critical step for initiating cancer cell proliferation. More importantly, both p56Lyn Y32 and MCM7 Y600 phosphorylation are enhanced in proliferating cancer cells and correlated with poor survival of breast cancer patients. These results suggest that Lyn is a critical EGFR downstream mediator and, therefore, is a promising therapeutic target in treating EGFR-activated cancers. • Contributed to several oncology projects resulting in seven publications including three Cancer Cell papers.

Postdoctoral scholar in Dr. Michael McManus’ laboratory. Led projects to investigate the biological significance of microRNAs in HER2/neu-associated tumorigenesis and identified a microRNA, miR-21, whose level was significantly elevated via the MAPK kinase pathway and played an essential role in the HER2/neu-mediated cancer cell invasion and resistance to trastuzumab therapy (first authored publication in Journal of Biological Chemistry with 246 citations).

Ph.D. graduate student in Dr. Sherie Morrison’s lab. • Innovated antibody and IFN-α fusion and demonstrated that a tumor-specific antibody fused with IFN-α is very efficient at targeting and killing tumor cells by inducing apoptosis and anti-tumor immune responses. This technology was licensed to Spectrum Pharmaceuticals for clinical development. • IGN002: comprises an anti-CD20 antibody attached to IFN-α through a stable peptide linker. Preclinical data showed that the targeting ability of IGN002 results in up to 10,000 fold higher than non-targeted IFN. IGN002 shows remarkable efficacy in rituximab-resistant tumor models and was under clinical studies for NHL patients. • Developed an anti-HER2/neu ScFv fusion with TNF-α and demonstrated that this fusion protein activated robust HER2/neu signaling and facilitated repair of injured human epithelia via its unique trimeric structure. • Four publications in major peer-reviewed journals (first and corresponding authored two publications).

Mentor: Dr. Mi-Hua Tao and collaboration with Dr. Ronald Levy at Stanford University. First authored publication in Blood- Created novel cancer immunotherapy by fusing CTLA-4 to an idiotypic antigen of B cell lymphoma. Demonstrated that fusion of CTLA-4 could dramatically enhance the immunogenicity of a non-immunogenic tumor antigen by targeting dendritic cells, thus initiating a potent anti-tumor T cells and B cells immune response in vivo.