Welcome to the Shanghai Recombinant Antibody Center (SRAC), ShanghaiTech University.
Antibody Molecules have emerged as one of the most promising therapeutic entities against cancers, infectious and inflammatory diseases. Traditional methods of generating antibodies were difficult and lack the scope of scalability. At Shanghai Recombinant Antibody Center (SRAC), we have developed high quality, very large and diverse synthetic human antibody repertoires for biologics drug discovery. This enormous synthetic antibody repertoire in various formats is displayed on M13-based phage display system which offers a scalable high-throughput screening of antibody drug leads against variety of target proteins. Shanghai Recombinant Antibody Center (SRAC) aspire to establish collaboration with academia and industry to provide antibody resource for developing high quality drug leads.
Shanghai Recombinant Antibody Center (SRAC) was founded in 2018 at the Shanghai Institute for Advanced Immunochemical studies (SIAIS), ShanghaiTech University. SRAC's mandate is to harness the basic research for the development of antibody drugs by setting up high value collaborative projects with academic labs and industries.
SRAC is led by renowned antibody scientist Prof. Sachdev S. Sidhu from University of Toronto and ShanghaiTech University. Under his leadership, SRAC has established a team of experienced antibody scientists for lead generation and validation. SRAC uses pioneering human synthetic antibody technology for developing antibody drugs. SRAC also has active collaborations with the HTS, Protein, Imaging, Analytical and Biomedical Big Data analysis technology platforms established in SIAIS. The highly optimized antibody technology and technological support at SIAIS gives SAC the leverage to lead antibody development space.
The SRAC is located within the REN Building in the beautiful campus of ShanghaiTech University. We welcome prospective partners for setting up collaborative research projects aiming for antibody drug development.
1.Libraries of synthetic antibodies:
A major advance in oncology over the last decade has been the emergence of monoclonal antibodies as effective therapeutics. Our lab has been involved in developing the latest frontier in antibody therapeutics: synthetic antibody libraries with man-made antigen-binding sites.
|[Fig1 – hybridoma vs. synthetic abs]: Construction of antibody libraries from natural or synthetic diversity. (a) Antibody libraries from natural repertoires are derived by harvesting VH and VL genes from naive B cells. B-cell maturation (1) involves the rearrangement of germline antibody genes in pro-B cells to produce naive B cells that contain diverse, functional antibody genes61. The gene encoding the heavy chain is formed first by the joining of three diversity elements (VH, D and JH), which together encode the variable domain, and a constant element (Cμ), which encodes the constant region of immunoglobulin M (IgM). Subsequently, the gene encoding a κ (shown) or λ light chain is formed by the joining of two diversity elements (Vκ and Jκ, or Vλ and Jλ for λ light chains) that encode the variable domain and a constant segment (Cκ or Cλ) that encodes the constant domain. Gene segments that encode leader sequences (L) direct secretion of both chains. For library construction, mRNA from naive B cells is reverse transcribed to produce cDNA (2). VH and VL repertoires are amplified from the cDNA using PCR (3), and these are combined in a phage-display vector (4) to produce phage-displayed antibody repertoires (5). (b) For the construction of synthetic antibody repertoires, insights from structural and functional analyses of functional antibodies (1) are used to design synthetic oligonucleotides (2) that introduce chemically and spatially defined diversity into the CDR loops (3). The synthetic CDR repertoires are incorporated into defined VH and VL framework genes in phage-display vectors (4) to produce phage-displayed antibody repertoires (5).|
|2. Alternative antibody frameworks:|
Synthetic antibody technology gives the freedom to explore other frameworks for their ability to bind antigens. The full-length antibody framework consists of a constant region (Fc) and a variable region (Fab).
|[Fig2 – structure of IgG and domains]: Crystal structure of a full-length antibody (IgG), a heterotetramer of two heavy chains (yellow) and two light chains (blue). The antigen-binding site (red) is formed by six hypervariable loops (three each from the light and heavy chain) or CDRs. The antigen-binding unit (Fab) can be reduced further to an Fv, consisting of a VL and VH monomer where the two variable domains are linked, producing a stable scFv. The simplest antigen-binding unit is the VH domain, found in natural camelid antibodies. For synthetic antibody library construction, diversity is introduced into the CDR loops, and the remaining regions of the variable domains serve as a framework to maintain the structure of the antigen-binding site.|
|3. Generation of synthetic antibodies by high throughput phage display selections:|
To produce synthetic antibodies, our antibody libraries are displayed on phage screened against a desired target antigen in an in vitro setting. Thus, this technology allows for rapid affinity maturation and specificity optimization of the selected antibodies.
|[Fig3-High throughput flowchart]: Flow chart summary of the high-throughput Fab generation process|
|4. Modulation of cell signaling with synthetic antibodies, and antibodies as potential therapeutics and reagents for biological research:|
Some of the best targets for antibodies are cell surface receptors involved in signal transduction pathways. Several of these pathways are deregulated in cancer and other diseases, and have been the target of chemical drugs for a number of years.
|FIG4-Immunofluorescence staining with Fab-YSv1 (red) performed on A673 cells expressing murine VEGFGFP (green). VEGF-GFP and Fab-YSv1 staining co-localize in the extracellular space formed between cell-to-cell contacts (merge, yellow). The Fab-YSv1 staining was completely abolished bypre-incubation of the antibody with excess recombinant hVEGF (C VEGF panels). The scale bar represents 20 mm. (d) Immunoprecipitations performed on media collected from metabolically labeled A673 cells. Fab-YSv1 and monoclonal antibody A4.6.1 show comparable specificity, as evidenced by identical patterns of bands for precipitated hVEGF isoforms. Anti-GFP polyclonal antibody was used as a negative control|