-Nature is our best inventor

our lab is interested in developing cutting-edge biotechnologies. Recently, fascinated by the exciting biomedical potentials of camelid single-chain VHH antibodies (so-called nanobodies), we have begun to develop methods and informatics to revolutionize the discovery and characterizations of nanobodies. In parallel, we are harnessing the fascinating biomolecules that we collected from Nature for advanced biomedical applications including disease diagnosis and treatment. Through collaboration with structural biologists and modelers, we are also interested in understanding the mechanisms of antigen-antibody binding. 

Our small team areworking on the following projects: 

1. Development of novel nanobody-based SARS-Cov-2 therapeutics. We have recently discovered thousands of potent SARS-CoV-2 neutralizing nanobodies (Nbs). We discovered multiple elite Nbs with up to femtomolar affinities (unprecedented for natural antibody fragments such as Nbs) that inhibit viral infection at sub-ng/ml concentration, more potent than some of the best human neutralizing antibodies. We determined a crystal structure of such an elite neutralizing Nb in complex with RBD. Structural proteomics and integrative modeling revealed multiple distinct and non-overlapping epitopes and indicated an array of potential neutralization mechanisms. Structural characterization facilitated the bioengineering of novel multivalent Nb constructs into multi-epitope cocktails that achieved ultrahigh neutralization potency (IC50s as low as 0.058 ng/ml- the most potent biotherapeutics to date) and may prevent mutational escape. Our thermostable Nbs can be rapidly produced in bulk from microbes and resist lyophilization, and aerosolization. These promising agents are readily translated into efficient, cost-effective, and convenient therapeutics to help end this once-in-a-century health crisis.

 

Our work has been reported by numerous journalists and media worldwide. We are interested in understanding the mechanisms of virus neutraliztion by structural biology approaches. Importantly, we are evaluating the preclinical efficacy of our Nb drugs in animal models towards clinical trials soon. 

 

 

 

 

2. Tools and informatics for large-scale, quantitative analysis of nanobody proteomes.

We have recently developed a proteomic strategy to survey, at an unprecedented scale, the landscapes of antigen-engaged, serum-circulating repertoires of camelid heavy-chain antibodies (hcAbs). The sensitivity and robustness of this technology were validated using three antigens spanning orders of magnitude in immune response; thousands of divergent, high-affinity hcAb families were confidently identified and quantified. Using high-throughput structural modeling, cross-linking mass spectrometry, mutagenesis, and deep learning, we mapped and analyzed the epitopes of > 100,000 antigen-antibody complexes.  In collaboration with Dina Schneidman's group, we have made some really interesting discoveries about how mammalian circulating antibodies recognize an antigen.

Check this out:  https://www.biorxiv.org/content/10.1101/2020.08.21.261917v1

 

 

Currently,  there are several directions that we are taking to move this technology forward. For example, we are interested in developing novel AI-based algorithms to facilitate nanobody discovery by proteomics. We are also exploring ways to humanize nanobodies.  Finally, we are developing tools to enable high-throughput screening and production of therapeutic biomolecules including but not limited to nanobodies.

3. Development of novel therapeutics for human diseases. 

Drug delivery and "Durakeukin"Therapeutic and diagnostic efficacies of numerous small biomolecules, nanobodies, and chemical compounds are hampered by the short half-lives. Here we developed a repertoire of diverse, high-affinity albumin-nanobodies (NbHSA) to facilitate drug delivery. By integrating biophysics, and hybrid structural biology, we have systematically characterized the Nb-HSA for albumin binding, mapped the epitopes, and resolved the architecture of a tetrameric Nb-albumin complex. We employed quantitative proteomics for accurate, multiplex Nb pharmacokinetic analysis. Using a humanized albumin mouse model, we found that the Nb-HSA has outstanding pharmacokinetics; the most stable Nb-HSA has a 771-fold T1/2 improvement compared with a control Nb. Interestingly, the pharmacokinetics of Nb-HSA is related to their biophysical and structural properties. To demonstrate the utility of NbHSA, we developed a highly stable Nb-HSA-hIL-2 cytokine conjugate “Duraleukin” and confirmed its improved anticancer properties than hIL-2 alone. We envision that this high-quality Nb resource will advance research into novel biotherapeutics.

Check out technology preprint here: https://www.biorxiv.org/content/10.1101/2020.08.19.257725v2.abstract

Currently, we are developing novel GPCR nanobodies and novel agents for brain applications. 

We'd like to thank the supports from 

© 2016-2019 by the Shi Lab University of Pittsburgh Pittsburgh PA 15213

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