THOMAS FUERST, Head of IBBR, Professor, Department of Cell Biology and Molecular Genetics

 

Research Interests:  Development of next generation vaccines and protein-based therapeutics for infectious disease and cancer. 

 

Dr. Fuerst’s group brings together an assemblage of scientific disciplines including virology, immunology, cell biology, chemistry, computational biology, and protein engineering.  The multidisciplinary programs include:  (1) a structure-based vaccine design program focused on enveloped viruses, (2) a scaffold-based protein therapeutics program focused on cancer targets, and (3) an immunoadjuvant and delivery program focused on polyphosphazene-based macromolecular delivery systems. 

 

The structure-based vaccine program is identifying and characterizing key antigenic determinants of enveloped viruses that correspond to protective immune responses.  Hepatitis C virus (HCV), a major human pathogen and a leading cause of liver cirrhosis, liver failure, and hepatocellular carcinoma, models the lead target virus for the program.  Although there are no clearly established in vitro correlates of protective immunity, multiple lines of evidence suggest that CD4+ and CD8+ T cell responses, while critical for controlling acute HCV infection, are inadequate for prevention of long-term viral persistence in most infected individuals.  Dr. Fuerst and colleagues are defining the structural and functional characteristics of conserved epitopes that are capable of eliciting protective antibodies in this highly diverse virus and are resistant to development of escape mutants.  This novel approach to develop a candidate vaccine by refocusing the immune response relies on the fundamental principles of structural vaccinology, i.e., understanding the nature of principal neutralizing determinants at the atomic level and refocusing the immune response for optimal presentation of a protective response.

 

The scaffold-based therapeutic program is developing powerful new classes of protein-based molecules that potentially bind with higher affinity and more specificity than conventional proteins to a target of interest.  Dr. Fuerst and colleagues are developing this multi-functional technology, referred to as SMART molecules, as multi-component protein machines with the potential to undergo allosteric changes in conformation in response to a binding event.  The binding-to-allosteric-change will then activate a catalytic response that has specificity to a target, and can act with low toxicity to reduce off target reactivity.  The group is developing the technology using HRAS, among the most frequently mutated oncogenes in cancer.  HRAS presents a model system for this technology as RAS proteins harboring oncogenic mutants invariably get stuck in an activated, GTP-bound state, causing hyperactivity of one of several well-defined downstream signaling pathways that drive tumorigenesis, growth, and metastasis of a variety of cancers, depending on which isoform harbors the mutation.  The SMART molecule in development is expected to sense subtle differences between normal versus oncogenic states and compute very different therapeutic responses.

 

The immunoadjuvant and delivery program is customizing a platform for synthesizing multifunctional, biodegradable classes of polymers well-suited for protein stabilization, antigen presentation, and delivery of macromolecules.  The group focuses on a unique class of polymer, polyphosphazene, which has a flexible phosphorus-nitrogen backbone and organic side groups.  Due to the specialized structural characteristics and synthetic approaches of polyphosphazenes, this class of polymer provides a combination of a biodegradable backbone with remarkable structural diversity enabling sensing of critical biological properties such as self-assembly with vaccine antigens, protein therapeutics, targeting capabilities, and environmentally triggered modulated release.  Dr. Fuerst and colleagues are focusing on immunoadjuvant properties for vaccine delivery and targeted nanoparticle delivery for protein-based therapeutics.

 

 

YUXING LI, Associate Professor, IBBR

 

Research interests:  Viral Immunology and HIV Vaccine Development

 

The long-term research interests of my lab include: (1) B cell response to viral infection; (2) HIV-1 vaccine development; and (3) HIV pathogenesis and anti-viral therapy. Currently, the research efforts of my lab at the Institute for Bioscience and Biotechnology Research (IBBR), University of Maryland, focus on investigating the development of B cell response targeting HIV envelope glycoproteins (Env) and searching for novel immunogen and immunization regimens to better elicit broadly neutralizing antibodies, funded by NIH/NIAID grants. Such studies aim to develop a better understanding of the mechanism underlying protective immunity and contribute to the development of a broadly effective HIV-1 vaccine. Rational design of Env immunogens and immunization regimens based on the B cell response analysis are actively progressing in my lab. Research on the reconstitution of immunity after anti-viral therapy and novel anti-viral approach development is also ongoing.

 

 

BRIAN PIERCE, Assistant Professor, IBBR and Cell Biology and Molecular Genetics

 

Research interests:  Computational modeling and design of immune recognition and vaccines

 

The Pierce laboratory uses structural bioinformatics and high resolution molecular modeling to provide new insights into immune recognition and host-pathogen interactions, and to design interfaces of therapeutic interest. Dr. Pierce has engineered several vaccine candidates for hepatitis C virus using structure-based design to focus immune response to a highly conserved B cell epitope in collaboration with MassBiologics, and is continuing research in this area at IBBR. Another area of interest in the Pierce lab is the design and modeling of T cell receptors (TCRs); this has resulted in a novel predictive TCR-peptide-MHC docking algorithm, TCRFlexDock, as well as several engineered TCRs, including a cancer therapeutic, with markedly higher affinity toward cognate peptide-MHCs. Other areas of interest include modeling the structural basis of viral variability and escape, and improved prediction of antibody recognition.

 

 

GILAD A. OFEK, Assistant Professor, IBBR and Cell Biology and Molecular Genetics

 

Research interests: Structural biology of enveloped viruses and recognition by molecules of the immune system

 

The Ofek lab’s research is focused on understanding the structural organization of viral surface glycoproteins and their recognition by protective antibodies. The lab employs the tools of structural biology to define critical interactions between antibodies and the viral glycoproteins they target, with a current focus on filoviruses and HIV. High-resolution antigenic maps that pinpoint specific regions on viral glycoproteins that are susceptible to effective immune attack are sought. Such structural information, especially obtained from antibodies that are broadly-protective, provides a template for rational design of vaccines and therapeutics aimed at inducing B cells that produce antibodies with similar efficacy upon vaccination. We have recently determined the co-crystal structure of a broadly protective antibody that targets a conserved region on the fusion loop of the glycoprotein, a region that is required for viral entry. The structure has defined a critical site of immune vulnerability on ebolaviruses as a whole that is being applied for development of broad vaccines and therapeutics. We are also isolating and characterizing novel antibodies against filovirus glycoproteins from multivalent immunization models with the goal of further exploring regions on the glycoproteins that confer broad antibody recognition. Domains on the glycoproteins that lead to ineffective immune responses are also of interest to define mechanisms of viral immune evasion. The developmental pathways by which B cells that produce the antibodies we study are being investigated in parallel to identify critical junctures in their functional maturation.