Dr. Sachdev (Dev) Sidhu’s research focuses on developing antibody therapeutics. His research has applications in cancer, infectious and chronic diseases and other disorders. Dr. Sidhu’s team continues to develop new technologies, including synthetic antibody libraries and new antibody formats that have been applied to create therapeutics for COVID-19 and treatment-resistant cancers.
- Synthetic antibody library development and design of antibody-derived molecules
- Therapeutic antibody development, with a focus on cancer and infectious disease applications
Development of potent and specific inhibitors and activators of enzyme activity by engineering variants of natural proteins
Therapeutic antibody development
Over the last 20 years, my group has has been involved in developing the latest frontier in antibody therapeutics: synthetic antibody libraries with man-made antigen-binding sites. These offer numerous advantages over hybridoma technology, and we have used our knowledge of antigen-antibody molecular interactions to develop highly functional repertoires that surpass the diversity and functionality of the natural immune system. We have integrated these libraries within a phage display system and optimized a high throughput methodology for the rapid discovery of antibodies to virtually any antigen and their structure-guided optimization. We also designed cell-based and virus-like particle antigen display methods for membrane-bound antigens, and are continuing to develop new libraries and explore new antibody formats, including single chain and multi-specific antibodies. Most recently, we have applied this technology to create candidate therapeutics for COVID-19 and treatment-resistant cancers.
Alternative scaffolds for protein inhibitors and potential therapeutics
We have developed a general strategy for developing potent and specific inhibitors and activators of enzyme activity by engineering variants of natural proteins that disrupt protein-protein interactions. We constructed phage-displayed ubiquitin variant libraries and generated inhibitors of dozens of human and viral ubiquitin ligases and deubiquitinases. These variants have been used for structural studies, as intracellular tools for the exploration of cell biology, and for target validation. We are continuously expanding the method to other protein scaffolds, including SH2 domains, cytokines, and hormones such as erythropoietin. We have also explored the use of D-amino acids for generating synthetic small protein modulators of protein activity, which represent a new class of potential therapeutics with low immunogenicity and longer half-lives.
Labriola, J. M., Miersch, S., Chen, G., Chen, C., Pavlenco, A., Saberianfar, R., Caccuri, F., Zani, A., Sharma, N., Feng, A., Leung, D. W., Caruso, A., Novelli, G., Amarasinghe, G. K. & Sidhu, S. S. (2022). Peptide-antibody fusions engineered by phage display exhibit an ultrapotent and broad neutralization of SARS-CoV-2 variants. ACS Chem. Biol. 17, 1978-88. PMID: 35731947.
Martyn, G. D., Veggiani, G., Kusebauch, U., Morrone, S. R., Yates, B. P., Singer, A. U., Tong, J., Manczyk, N., Gish, G., Sun, Z., Kurinov, I., Sicheri, F., Moran, M. F., Moritz, R. L., & Sidhu, S. S. (2022). Engineered SH2 domains for targeted phosphoproteomics. ACS Chem. Biol. 17, 1472-84. PMID: 35613471.
Veggiani, G., Yates, B. P., Martyn, G. D., Manczyk, N., Singer, A. U., Kurinov, I., Sicheri, F. & Sidhu, S. S. (2022). Panel of engineered ubiquitin variants targeting the family of human ubiquitin interacting motifs. ACS Chem Biol. 17, 941-56. PMID: 35385646.
Tang, J. Q., Veggiani, G., Singer, A., Teyra, J., Chung, J. & Sidhu, S. S. (2021). A panel of engineered ubiquitin variants targeting the family of domains found in ubiquitin specific proteases (DUSPs). J. Mol. Biol. 433, 167300. PMID: 34666042.
Nilvebrant, J., Ereño-Orbea, J., Gorelik, M., Julian, M. C., Tessier, P. M., Julien, J. P., & Sidhu, S. S. (2021). Systematic engineering of optimized autonomous heavy-chain variable domains. J. Mol. Biol. 433, 167241. PMID: 34508727.
Miersch, S., Li, Z., Saberianfar, R., Ustav, M., Case, J. B., Blazer, L., Chen, C., Ye, W., Pavlenco, A., Gorelik, M., Garcia Perez, J., Subramania, S., Singh, S., Ploder, L., Ganaie, S., Chen, R. E., Leung, D. W., Pandolfi, P. P., Novelli, G., Matusali, G., Colavita, F., Capobianchi, M. R., Jain, S., Gupta, J. B., Amarasinghe, G. K., Diamond, M. S., Rini, J. & Sidhu, S. S. (2021). Tetravalent SARS-CoV-2 neutralizing antibodies show enhanced potency and resistance to escape mutations. J. Mol. Biol. 433, 167177. PMID: 34329642.
Gallo, E., Kelil, A., Haughey, M., Cazares-Olivera, M., Yates, B. P., Zhang, M., Wang, N. Y., Blazer, L., Carderelli, L., Adams, J. J., Kossiakoff, A. A., Wells, J. A., Xie, W., & Sidhu, S. S. (2021). Inhibition of cancer cell adhesion, migration and proliferation by a bispecific antibody that targets two distinct epitopes on αv integrins. J. Mol. Biol. 433, 167090. PMID: 34090922.
Kelil, A., Gallo, E., Banerjee, S., Adams, J. J. & Sidhu, S. S. (2021). CellectSeq: In silico discovery of antibodies targeting integral membrane proteins combining in situ selections and next-generation sequencing. Commun. Biol. 4, 561. PMID: 33980972.
Marinec, P. S., Landgraf, K. E., Uppalapati, M., Chen, G., Xie, D., Jiang, Q., Zhao, Y., Petriello, A., Deshayes, K., Kent, S. B., H., Ault-Riche, D. & Sidhu, S. S. (2021). A non-immunogenic bivalent d-protein potently inhibits retinal vascularization and tumor growth. ACS Chem. Biol. 16, 548-56. PMID: 33621466.
Enderle, L., Shalaby, K. H., Gorelik, M., Weiss, A., Blazer, L. L., Paduch, M., Cardarelli, L., Kossiakoff, A., Adams, J. J. & Sidhu, S. S. (2021). A T cell redirection platform for co-targeting dual antigens on solid tumors. MAbs 13, 1933690. PMID: 34190031.
Garg, P., Ceccarelli, D. F., Keszei, A. F., Kourinov, I., Sicheri, F. & Sidhu, S. S. (2020). Structural and functional analysis of ubiquitin-based inhibitors that target the backsides of E2 enzymes. J. Mol. Biol. 432, 952-66. PMID: 31634471.
Chen, G., Karauzum, H., Long, H., Carranza, D., Holtsberg, F. W., Howell, K. A., Abaandou, L., Zhang, B., Jarvik, N., Ye, W., Liao, G. C., Gross, M. L., Leung, D. W., Amarasinghe, G. K., Aman, M. J. & Sidhu, S. S. (2019) Potent neutralization of staphylococcal enterotoxin B in vivo by antibodies that block binding to the T-cell receptor. J. Mol. Biol. 431, 4354-67. PMID: 30928493.
Tao, Y., Mis, M., Blazer, L., Ustav Jr, M., Steinhart, Z., Chidiac, R., Kubarakos, K., O’Brien, S., Wang, X., Jarvik, N., Patel, N., Adams, J., Moffat, J., Angers, S. & Sidhu, S. S. (2019). Tailored tetravalent antibodies potently and specifically activate Wnt/Frizzled pathways in cells, organoids and mice. Elife 8, e46134. PMID: 31452509.
Teyra, J., Singer, A. U., Schmitges, F. W., Jaynes, P., Kit Leng Lui, S., Polyak, M. J., Fodil, N., Krieger, J. R., Tong, J., Schwerdtfeger, C., Brasher, B. B., Ceccarelli, D. F. J., Moffat, J., Sicheri, F., Moran, M. F., Gros, P., Eichhorn, P. J. A., Lenter, M., Boehmelt, G. & Sidhu, S.S. (2019) Structural and functional characterization of ubiquitin variant inhibitors of USP15. Structure 27, 590-605. PMID: 30713027.
Turowec, J. P., Lau, E. W. T., Wang, X., Brown, K. R., Fellouse, F. A., Jawanda, K. K., Pan, J., Moffat, J. & Sidhu, S. S. (2019) Functional genomic characterization of a synthetic anti-HER3 antibody reveals a role for ubiquitination by RNF41 in the anti-proliferative response. J. Biol. Chem. 294, 1396-409. PMID: 30523157.
Awards and Distinctions
2020 National Academy of Inventors Fellowship
2015 Protein Society’s Christian B. Anfinsen Award (technological achievement or significant methodological advances in the field of protein science)
2012 University of Toronto Inventor of the Year Award (Biomedical and Life Science)
University of Waterloo Affiliations
- Co-Director, the Anvil Institute
Professional Associations and Service
Dr. Sidhu serves on the editorial boards of the Journal of Molecular Biology, Chemical Biology & Drug Design, and Antibodies. He is on the Scientific Advisory Board of Cambridge Health Institute’s “Phage Display Therapeutics Conference” and on the Organizing Committee of the FEBS Workshop on Modular Protein Domains. He is a member of the Protein Society (proteinsociety.org) and the American Society for Biochemistry and Molecular Biology (ASBMB, asbmb.org).
- 1990 BSc Biochemistry (Simon Fraser University)
- 1996 PhD Biochemistry (Simon Fraser University)
- 1998 Postdoctoral Fellowship Protein Engineering (Genentech, Inc.)