Dr. Zhang received his B.S. in Biological Sciences from Shandong University in 2003 and his M.S. in Biophysics from University of Guelph in 2006. He earned his Ph.D. in Biochemistry with Professor Vern L. Schramm at Albert Einstein College of Medicine in 2011. His doctoral research was focused on the enzymatic transition state and catalytic mechanism for rational design of potent enzyme inhibitors as antimalarial and anticancer drugs. Dr. Zhang received postdoctoral training with Professor Peter G. Schultz at the Scripps Research Institute and California Institute for Biomedical Research (Calibr) from 2011 to 2014. His postdoctoral work established a versatile approach to the generation of novel antibody chimeras with excellent physical, biological, and pharmacological properties for drug development. Dr. Zhang joined the faculty in the Department of Pharmacology and Pharmaceutical Sciences at USC School of Pharmacy as an Assistant Professor in December 2014.
Areas of Expertise (8)
Cancer, Diabetes and Neurodegeneration
Drug Design and Discovery
2020 Maximizing Investigators' Research Award (MIRA)
National Institute of General Medical Sciences (NIGMS) of National Institutes of Health (NIH)
2019 New Investigator Award
Tobacco-Related Disease Research Program (TRDRP)
2019 Innovative Development and Exploratory Award (IDEA)
California Breast Cancer Research Program
2019 AACR-Bayer Innovation and Discovery Grant
American Association for Cancer Research (AACR)
2019 Career Development Award
Department of Defense (DoD) Congressionally Directed Medical Research Programs (CDMRP)
2019 The V Scholar PLUS Award
The V Foundation for Cancer Research
2018 Research Starter Grant in Translational Medicine and Therapeutics
Pharmaceutical Research and Manufacturers of America (PhRMA) Foundation
2017 Research Career Development Award
2017 New Investigator Grant
American Association of Pharmaceutical Scientists (AAPS) Foundation
2016 The V Scholar Award
The V Foundation for Cancer Research
The Scripps Research Institute and California Institute for Biomedical Research: Postdoctoral Research, Chemical Biology 2014
Albert Einstein College of Medicine: Ph.D., Biochemistry 2011
University of Guelph: M.S., Biophysics 2006
Shandong University: B.S., Biological Sciences 2003
- American Chemical Society
- American Association of Pharmaceutical Scientists
- American Association for Cancer Research
Selected Media Appearances (8)
Zhang Awarded $1.9 Million NIH Grant
USC School of Pharmacy online
Yong (Tiger) Zhang, PhD, assistant professor of pharmacology and pharmaceutical sciences at the USC School of Pharmacy, was awarded a five-year, $1.9 million National Institutes of Health (NIH) grant for his project entitled “Chemistry and Biology of ADP-Ribosylation-Dependent Signaling.”
New method of manufacturing targeted drugs could lead to better cancer treatments
The current way to make a highly targeted type of drug called “antibody-drug conjugates” is lengthy and inefficient. Scientists at the USC School of Pharmacy have engineered something better.
$990,000 New Investigator Grant Awarded to Zhang
USC School of Pharmacy online
Yong (Tiger) Zhang, PhD, assistant professor of pharmacology and pharmaceutical sciences at the USC School of Pharmacy, was awarded a three-year, $990,000 New Investigator Award by Tobacco-Related Disease Research Program (TRDRP) of California.
DOD Grant Awarded to Zhang
USC School of Pharmacy online
Yong (Tiger) Zhang, PhD, was awarded a three-year, Career Development Award grant in the amount of $593,996 from the Department of Defense Congressionally Directed Medical Research Programs.
Yong (Tiger) Zhang Awarded USC Stevens Technology Advancement Grant
USC School of Pharmacy online
Yong (Tiger) Zhang, assistant professor of pharmacology and pharmaceutical sciences at the USC School of Pharmacy, received a $50,000 Technology Advancement Grant (TAG) from the USC Stevens Center.
Zhang Awarded 2017 AAPS New Investigator Grant for Colorectal Cancer Research
USC School of Pharmacy online
Yong (Tiger) Zhang, PhD, assistant professor of pharmacology and pharmaceutical sciences at the USC School of Pharmacy, was awarded the 2017 New Investigator Grant by the American Association of Pharmaceutical Scientists (AAPS) Foundation.
Meet Yong Zhang
AAPS Foundation print
A 2017 AAPS Foundation New Investigator Grant recipient shares his research with immuno-nanoparticles.
Zhang Awarded $200,000 Grant from V Foundation for Cancer Research
USC School of Pharmacy online
Yong (Tiger) Zhang, PhD, was awarded a two-year $200,000 grant from the V Foundation for Cancer Research as a V Foundation Scholar.
Research Focus (1)
Research in the Zhang Lab
Protein post-translational modifications (PTMs) result in critical changes on protein structure and biological function. The broad range of PTMs observed on various proteins vastly diversifies the inventory of organism proteome. Furthermore, highly abundant PTMs with dynamic pattern play essential and complex roles in biological processes. Our laboratory is very interested in developing innovative technologies to systematically dissect PTMs essential for cancer, inflammation, neurodegeneration and immune disorders for understanding the functional consequences and regulatory mechanisms of PTMs and for discovery of novel therapeutic targets and drug inhibitors. Antibody recognizes and neutralizes foreign pathogens and is an important component in immune system. The exquisite specificity and tight-binding affinity of monoclonal antibodies make antibody-based therapeutics ideal drug candidates. Development of monoclonal antibodies against ligands, receptors, and protein-protein interactions that play critical roles in various human diseases allows discovery of powerful therapeutic agents with minimum off-target effects. We are aimed at designing potent monoclonal antibodies with high specificity as novel immunotherapeutic tools for cancer, immune disorders, neurodegenerative, and infectious diseases, and developing new and robust protein engineering approaches for efficient generation of potent polypeptide-based diagnostics and therapeutics. Graduate students can receive direct and extensive training from PI in antibody engineering, enzymology and catalysis, inhibitor design and synthesis, protein expression, purification and characterization, cell culturing, assay development, proteomics, X-ray crystallography and NMR, pharmacokinetics and pharmacodynamics, and high-throughput screening. Upon graduation, students are expected to possess multiple sets of skills and strong publication record, essential for career development in both academia and industry.
Selected Articles (11)
A Poly-ADP-Ribose Polymer-Based Antibody-Drug ConjugateChem. Sci.
2020 Protein poly-ADP-ribosylation (PARylation) plays vital roles in many aspects of physiology and pathophysiology. This posttranslational modification is catalyzed by poly-ADP-ribose polymerases (PARPs) through additions of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to protein residues, forming linear or branched poly-ADP-ribose (PAR) polymers. In this study, we explored a new concept of utilizing functionalized PAR polymers for targeted drug delivery. This was achieved by rapid and efficient generation of auto-PARylated PARP1 with 3′-azido ADP-riboses and subsequent conjugations of anti-human epidermal growth factor receptor 2 (HER2) antibodies and monomethyl auristatin F (MMAF) payloads. This designed PARylated PARP1-antibody-MMAF conjugate could potently kill HER2-expressing cancer cells in high specificity. This proof-of-principle work demonstrates the feasibility of production of PAR polymer-based antibody-drug conjugate and its application in targeted delivery. The PAR polymer-based conjugates may lead to new types of therapeutics with potentially improved physicochemical and pharmacological properties.
A Humanized Antibody Inhibitor for Cathepsin LProtein Sci.
2020 Cathepsin L (CTSL) is a cysteine protease involved in a variety of physiological and pathological processes. Potent inhibitors against CTSL have long been sought for drug development. Due to insufficient specificity and suboptimal pharmacological properties for current CTSL inhibitors, novel agents are still required for selectively blocking CTSL activity. Here we generated a humanized antibody inhibitor of CTSL by genetically fusing the inhibitory propeptide of procathepsin L to the N‐terminus of the light chain of a humanized antibody. The resulting antibody fusion could be stably expressed and displays highly potent inhibition activity and specificity toward CTSL. This work demonstrates a new approach for the rapid generation of antibody inhibitors of CTSL. It can possibly be extended to create inhibitory antibodies targeting other cathepsin proteases, providing novel research and therapeutic tools.
Synthesis of Site-Specific Antibody-Drug Conjugates by ADP-Ribosyl Cyclases.Sci. Adv.
2020 Most of the current antibody-drug conjugates (ADCs) in clinic are heterogeneous mixtures. To produce homogeneous ADCs, established procedures often require multiple steps or long reaction times. The introduced mutations or foreign sequences may cause high immunogenicity. Here, we explore a new concept of transforming CD38 enzymatic activity into a facile approach for generating site-specific ADCs. This was achieved through coupling bifunctional antibody-CD38 fusion proteins with designer dinucleotide-based covalent inhibitors with stably attached payloads. The resulting adenosine diphosphate–ribosyl cyclase–enabled ADC (ARC-ADC) with a drug-to-antibody ratio of 2 could be rapidly generated through single-step conjugation. The generated ARC-ADC targeting human epidermal growth factor receptor 2 (HER2) displays excellent stability and potency against HER2-positive breast cancer both in vitro and in vivo. This proof-of-concept study demonstrates a new strategy for production of site-specific ADCs. It may provide a general approach for the development of a novel class of ADCs with potentially enhanced properties.
Rational Design of a Humanized Antibody Inhibitor of Cathepsin B.Biochemistry
2020 Cathepsin B (CTSB) is an abundant cysteine protease that functions in both endolysosomal compartments and extracellular regions. A considerable number of preclinical and clinical studies indicate that CTSB is implicated in many human diseases. Expression levels and activity of CTSB significantly correlate with disease progression and severity. Current inhibitors of CTSB are lack of adequate specificity and pharmacological activities. Through structure-guided rational design, we hereby designed and generated a humanized antibody inhibitor targeting human CTSB. This was achieved by genetically fusing the propeptide of procathepsin B, a naturally occurring inhibitor of CTSB, into heavy chain complementarity-determining region 3 (CDR3H) of Herceptin that is used in the clinic for the treatment of breast cancer. The resulting antibody-propeptide fusion displayed high specificity for inhibiting CTSB proteolytic activity at nanomolar levels. Pharmacokinetic studies in mice revealed a plasma half-life of approximately 42 h for this anti-CTSB antibody inhibitor, comparable to that of the parental Herceptin scaffold. This study demonstrates a new approach for the efficient generation of humanized antibody inhibitors with high potency and specificity for human CTSB, which may be extended to develop antibody inhibitors against other disease relevant cathepsin proteases.
Genetically Engineered Cell-Derived Nanoparticles for Targeted Breast Cancer Immunotherapy.Mol. Ther.
2019 Exosomes are nanosized membranous vesicles secreted by a variety of cells. Due to their unique and pharmacologically important properties, cell-derived exosome nanoparticles have drawn significant interest for drug development. By genetically modifying exosomes with two distinct types of surface-displayed monoclonal antibodies, we have developed an exosome platform termed synthetic multivalent antibodies retargeted exosome (SMART-Exo) for controlling cellular immunity. Here, we apply this approach to human epidermal growth factor receptor 2 (HER2)-expressing breast cancer by engineering exosomes through genetic display of both anti-human CD3 and anti-human HER2 antibodies, resulting in SMART-Exos dually targeting T cell CD3 and breast cancer-associated HER2 receptors. By redirecting and activating cytotoxic T cells toward attacking HER2-expressing breast cancer cells, the designed SMART-Exos exhibited highly potent and specific anti-tumor activity both in vitro and in vivo. This work demonstrates preclinical feasibility of utilizing endogenous exosomes for targeted breast cancer immunotherapy and the SMART-Exos as a broadly applicable platform technology for the development of next-generation immuno-nanomedicines.
A Ribose-Functionalized NAD+ with Unexpected High Activity and Selectivity for Protein Poly-ADP-Ribosylation.Nat. Commun.
2019 Nicotinamide adenine dinucleotide (NAD+)-dependent ADP-ribosylation plays important roles in physiology and pathophysiology. It has been challenging to study this key type of enzymatic post-translational modification in particular for protein poly-ADP-ribosylation (PARylation). Here we explore chemical and chemoenzymatic synthesis of NAD+ analogues with ribose functionalized by terminal alkyne and azido groups. Our results demonstrate that azido substitution at 3′-OH of nicotinamide riboside enables enzymatic synthesis of an NAD+ analogue with high efficiency and yields. Notably, the generated 3′-azido NAD+ exhibits unexpected high activity and specificity for protein PARylation catalyzed by human poly-ADP-ribose polymerase 1 (PARP1) and PARP2. And its derived poly-ADP-ribose polymers show increased resistance to human poly(ADP-ribose) glycohydrolase-mediated degradation. These unique properties lead to enhanced labeling of protein PARylation by 3′-azido NAD+ in the cellular contexts and facilitate direct visualization and labeling of mitochondrial protein PARylation. The 3′-azido NAD+ provides an important tool for studying cellular PARylation.
Reprogramming Exosomes as Nanoscale Controllers of Cellular Immunity.J. Am. Chem. Soc.
2018 Exosomes are naturally occurring membranous vesicles secreted by various types of cells. Given their unique and important biological and pharmacological properties, exosomes have been emerging as a promising form of nanomedicine acting via efficient delivery of endogenous and exogenous therapeutics. Here we explore a new concept of utilizing endogenously derived exosomes as artificial controllers of cellular immunity to redirect and activate cytotoxic T cells toward cancer cells for killing. This was achieved through genetically displaying two distinct types of antibodies on exosomal surface. The resulting synthetic multivalent antibodies retargeted exosomes (SMART-Exos), which express monoclonal antibodies specific for T-cell CD3 and cancer cell-associated epidermal growth factor receptor (EGFR), were shown to not only induce cross-linking of T cells and EGFR-expressing breast cancer cells but also elicit potent antitumor immunity both in vitro and in vivo. This proof-of-concept study demonstrates a novel application of exosomes in cancer immunotherapy and may provide a general and versatile approach for the development of a new class of cell-free therapy.
Facile Chemoenzymatic Synthesis of a Novel Stable Mimic of NAD+.Chem. Sci.
2018 Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor participating in a variety of important enzyme-catalyzed physiological and pathophysiological processes. Analogues of NAD+ provide key and valuable agents for investigating NAD+-dependent enzymes. In this study, we report the preparation of a novel stable NAD+ mimic, 4′-thioribose NAD+ (S-NAD+), using a facile and efficient chemoenzymatic approach. Substrate activity assays indicated the resulting S-NAD+ is chemically inert to human CD38 and sirtuin 2 enzymes, but capable of participating in redox reactions in a manner similar to NAD+. X-ray crystallographic analysis revealed binding of S-NAD+ to the active site of human CD38 and critical residues involved in leaving group activation and catalysis. By more closely mimicking NAD+ in geometry and electrostatics, the generated S-NAD+ offers a unique and important tool that can be extended to study enzymes utilizing NAD+.
A Macrodomain-Linked Immunosorbent Assay (MLISA) for Mono-ADP-Ribosyltransferases.Anal Biochem.
2017 ADP-ribosyltransferases (ARTs) catalyze reversible additions of mono- and poly-ADP-ribose onto diverse types of proteins by using nicotinamide adenine dinucleotide (NAD+) as a cosubstrate. In the human ART superfamily, 14 out of 20 members are shown to catalyze endogenous protein mono-ADP-ribosylation and play important roles in regulating various physiological and pathophysiological processes. Identification of new modulators of mono-ARTs can thus potentially lead to discovery of novel therapeutics. In this study, we developed a macrodomain-linked immunosorbent assay (MLISA) for characterizing mono-ARTs. Recombinant macrodomain 2 from poly-ADP-ribose polymerase 14 (PARP14) was generated with a C-terminal human influenza hemagglutinin (HA) tag for detecting mono-ADP-ribosylated proteins. Coupled with an anti-HA secondary antibody, the generated HA-tagged macrodomain 2 reveals high specificity for mono-ADP-ribosylation catalyzed by distinct mono-ARTs. Kinetic parameters of PARP15-catalyzed automodification were determined by MLISA and are in good agreement with previous studies. Eight commonly used chemical tools for PARPs were examined by MLISA with PARP15 and PARP14 in 96-well plates and exhibited moderate inhibitory activities for PARP15, consistent with published reports. These results demonstrate that MLISA provides a new and convenient method for quantitative characterization of mono-ART enzymes and may allow identification of potent mono-ART inhibitors in a high-throughput-compatible manner.
Rational Design of Humanized Dual-Agonist Antibodies.J. Am. Chem. Soc.
2015 The ultralong heavy chain complementarity determining region 3 (CDR3H) of bovine antibody BLV1H12 folds into a novel “stalk-knob” structural motif and has been exploited to generate novel agonist antibodies through replacement of the “knob” domain with cytokines and growth factors. By translating this unique “stalk-knob” architecture to the humanized antibody trastuzumab (referred to hereafter by its trade name, Herceptin, Genentech USA), we have developed a versatile approach to the generation of human antibody agonists. Human erythropoietin (hEPO) or granulocyte colony-stimulating factor (hGCSF) was independently fused into CDR3H, CDR2H, or CDR3L of Herceptin using an engineered “stalk” motif. The fusion proteins express in mammalian cells in good yields and have similar in vitro biological activities compared to hEPO and hGCSF. On the basis of these results we then generated a bi-functional Herceptin-CDR fusion protein in which both hEPO and hGCSF were grafted into the heavy- and light-chain CDR3 loops, respectively. This bi-functional antibody fusion exhibited potent EPO and GCSF agonist activities. This work demonstrates the versatility of the CDR-fusion strategy for generating functional human antibody chimeras and provides a novel approach to the development of multi-functional antibody-based therapeutics.
Rational Design of a Humanized Glucagon‐Like Peptide‐1 Receptor Agonist Antibody.Angew. Chem. Int. Ed. Engl.
2015 Bovine antibody BLV1H12 possesses a unique “stalk–knob” architecture in its ultralong heavy chain CDR3, allowing substitutions of the “knob” domain with protein agonists to generate functional antibody chimeras. We have generated a humanized glucagon‐like peptide‐1 (GLP‐1) receptor agonist antibody by first introducing a coiled‐coil “stalk” into CDR3H of the antibody herceptin. Exendin‐4 (Ex‐4), a GLP‐1 receptor agonist, was then fused to the engineered stalk with flexible linkers, and a Factor Xa cleavage site was inserted immediately in front of Ex‐4 to allow release of the N‐terminus of the fused peptide. The resulting clipped herceptin–Ex‐4 fusion protein is more potent in vitro in activating GLP‐1 receptors than the Ex‐4 peptide. The clipped herceptin–Ex‐4 has an extended plasma half‐life of approximately four days and sustained control of blood glucose levels for more than a week in mice. This work provides a novel approach to the development of human or humanized agonist antibodies as therapeutics.