Li's Laboratory

　　　　　　　　 Principal Investigator



Yi Li gained his medical degree in 1987 at Hunan Medical University (formally Hsiang-Ya Medical College, College of Yale-in-China), ChangSha, China. He had been a physician in China for 4 years before visiting Immunology Department, St Mary Hospital in Manchester, UK in 1991. He finished his Ph.D. in antibody engineering at the University of Leicester, UK. After a one-year post-doctor training in 1996, he had been research scientist, department head or director for several companies, including Immunocore/Medigen/Avidex, Biovation/Meck KgA and ADAS UK.  he has jointed Chinese Academy of Sciences, Guangzhou Institutes of Biomedicine and Health (GIBH), and State Key Laboratory of Respiratory Disease, Guangzhou Medical University, and been currently holding positions of Principal Investigator, Director of Joint Laboratories of GIBH-XiangXue Pharmaceutical co. ltd

In order to build a world class research team, we have recruited Associate Principal Investigators (Dr Zhang Hua Jun, Xu Xin Ping), Assistant Investigators (Dr Liang Zhao Duan, Dr Liu XiaoPing, Cai Wen Xuan) and Research Assistance(Tian Ye, Li You Jia, Wang Zhu, Wu AnAn, Bao Yi Feng，Lu Chun Ni). They are specialized in various fields, including molecular biology and biochemistry (ZHJ, CWX, BYF, LCN, WZ), biophysics (TY, XXP), cellular immunology (LZD,LXP, LYJ, WAA).

Our groups’ major research interest is to establish the fundamental understanding of new biologics and cellular therapy for cancer, viral infection and autoimmune disease. We have paid particular attention on how to harness immune system to deal these medical problems. For example, we are trying to develop a new class of biologics namely high affinity T cell receptors (HATs). In the majority of patients, there is a failure of immune recognition and activation, often through disease specific immune escape mechanisms. However, CTLs may potentially attack and eradicate malignant or viral infected cells leading to clinical remission or cure, so HAT is generated for exploiting the power of patient’s CTLs. On the other hand, from the immune system, naturally isolated soluble wild-type TCRs are very low affinity and therefore unsuitable for targeting therapeutic use. HAT is generated from the naturally isolated low affinity TCR by increase its affinity over million fold using phage display. In order to redirect the patients CTLs against targeted diseased cells, we can fuse an anti-CD3 scFv to the HATs to create bi-functional proteins, or HATacs. HATacs guide CTL attack the disease cell via the antibody fragment. The HATac guided CTL response will built as both highly specific and potent, leading to CTL mediated destruction of target cells presenting just 30-50 copies of peptide-MHC complex. The HATac guided CTLs should be able to kill numerous target cells in a serial fashion.

The second research interest in our groups is to investigate the structural mechanism of TCR binding to its antigen. We pay particular attention on the structural evolution characteristics and the structure-function relations. T cell receptor (TCR) plays a key role in adaptive immune system, and is the major antigen recognition molecule, which can mediate T cell to kill tumor cells or virus infected cells. However, there are still some important questions need to be answered. For example, there is no reported mechanism of TCR specificity change in the peripheral environment after the V(D)J gene arrangement in the thymus, on the other hand, the total number of T cells is limited and much less than the amount of antigens that could be recognized by T cells. What is the reason that relative more antigens could be recognized by limited T cells? We postulate the plasticity of TCR is the most likely answer for this question. The research will try to reveal a fundamental immunological conundrum and providing valuable information to design better molecules for immunotherapy.

Publications: 

1. Liddy, N., Bossi, G., Adams, K. J., Lissina, A., Mahon, T. M., Hassan, N. J., Gavarret, J., Bianchi, F. C., Pumphrey, N. J., Ladell,  K., Gostick, E., Sewell, A. K., Lissin, N. M., Harwood, N. E., Molloy, P. E., Li, Y*., Cameron, B. J., Sami, M., Baston, E. E., Todorov, P. T., Paston, S. J., Dennis, R. E., Harper, J. V., Dunn, S. M., Ashfield, R., Johnson, A., McGrath, Y., Plesa, G., June, C. H., Kalos, M., Price, D. A., Vuidepot, A., Williams, D. D., Sutton, D. H., Jakobsen. B. K. (2012) Monoclonal TCR-redirected tumour cell killing. Nature Medicine 18(6), 980-7  (*supervisor of Liddy, N)

2. Liddy, N., P. E. Molloy, Bennett, A. D.，Boulter, J. M.， Jakobsen, B. K.， Li, Y*. (2010). Production of a soluble disulfide bond-linked TCR in the cytoplasm of Escherichia coli trxB gor mutants. Mol Biotechnol 45 (2): 140-9. （*corresponding author）

3. Moysey RK*, Li Y*, Paston SJ, Baston EE, Sami MS, Cameron BJ, Gavarret J, Todorov P, Vuidepot A, Dunn SM, Pumphrey NJ, Adams KJ, Yuan F, Dennis RE, Sutton DH, Johnson AD, Brewer J E, Ashfield R, Lissin NM and Jakobsen BK，(2010) High affinity soluble ILT2 receptor: a potent inhibitor of CD8(+) T cell activation, Protein Cell, 1, 12, 1118-27. (*.joint first author)

4. Li, Y., Moysey, R., Molloy, P. E., Vuidepot, A. L., Mahon, T., Baston, E., Dunn, S., Liddy, N., Jacob, J., Jakobsen, B. K. & Boulter, J. M. (2005). Directed evolution of human T-cell receptors with picomolar affinities by phage display. Nature Biotechnol.23, 349-54

5.Varela-Rohena, A., Molloy, P.E., Dunn, S.M., Li, Y., Suhoski, M.M., Carroll, R.G., Milicic, A., Mahon, T., Sutton, D.H., Lauge, B.E., Moysey, R., Cameron, B.J. Vuidepot, A., Purbhoo, M.E., Cole, D.K. Phillips, R.E., June, C.H., Jakobsen, B.K., Sewell, A.K., Riley, J.L. (2008) Control of HIV-1 immune escape by CD8 T-cells expressing enhanced T-cell receptor. Nature Medicine,14(12), 1390-1395

6.Purbhoo*, M. A.; Li*, Y.; Sutton*, D. H.; Brewer, J. E.; Gostick, E.; Bossi, G.; Laugel, B.; Moysey, R.; Baston, E.; Liddy, N.; Cameron, B.; Bennett, A. D.; Ashfield, R.; Milicic, A.; Price, D. A.; Classon, B. J.; Sewell, A. K.; Jakobsen, B. K.(2007) The HLA A*0201-restricted hTERT(540-548) peptide is not detected on tumor cells by a CTL clone or a high-affinity T-cell receptor. Mol Cancer Ther. 6: 2081-91 (*joint first author).

7.Dunn, SM, Rizkallah, PJ, Baston, E, Mahon, T, Moysey, R, Gao, F, Sami, M, Boulter, J, Li, Y, & Jakobsen, BK. (2006) Direct evolution of human T cell receptor CDR2 residues by phage display dramatically enhances affinity for cognate peptide-MHC without increasing cross-reactivity. Protein Science, 15, 710-21

8.Zhao, Y.; Bennett, A. D.; Zheng, Z.; Wang, Q. J.; Robbins, P. F.; Yu, L. Y.; Li, Y.; Molloy, P. E.; Dunn, S. M.; Jakobsen, B. K.; Rosenberg, S. A.; Morgan, R. A.(2007) High-Affinity TCRs Generated by Phage Display Provide CD4+ T Cells with the Ability to Recognize and Kill Tumor Cell Lines, J Immunol. 179: 5845-54

9.Sami, M.; Rizkallah, P. J.; Dunn, S.; Molloy, P.; Moysey, R.; Vuidepot, A.; Baston, E.; Todorov, P.; Li, Y.; Gao, F.; Boulter, J. M.; Jakobsen, B. K.(2007) Crystal structures of high affinity human T-cell receptors bound to peptide major histocompatibility complex reveal native diagonal binding geometry. Protein Eng Des Sel. 20: 397-403

10.Laugel, B., Boulter, J. M., Lissin, N., Vuidepot, A., Li, Y., Gostick, E., Crotty, L. E., Douek, D. C., Hemelaar, J., Price, D. A., Jakobsen, B. K. & Sewell, A. K. (2005). Design of soluble recombinant T cell receptors for antigen targeting and T cell inhibition. J Biol Chem 280, 1882-92.

11.Li, Y., Collins, M. S., Whitelam, G. C. & Alexander, D. J. (2002). Rapid pathotyping of Newcastle disease virus using a single-chain Fv displayed on phage against the C-terminal end of the F2 polypeptide. Arch Virol 147, 2025-37.

12.Gough, K. C., Li, Y. & Whitelam, G. C., in　 edited by. vol. (2002). Antibody Phage Display Libraries. In Molecular plant biology: A practical approach (Gilmartin, P., ed.), Vol. 2, pp. 221-236. Oxford University Press.

13.Li, Y*., Kilpatrick, J. & Whitelam, G. C. (2000). Sheep monoclonal antibody fragments generated using a phage display system. J Immunol Methods 236, 133-46. （* corresponding author）

14.Li, Y*., Cockburn, W., Kilpatrick, J. B. & Whitelam, G. C. (2000). High affinity ScFvs from a single rabbit immunized with multiple haptens. Biochem Biophys Res Commun 268, 398-404. （* corresponding author）

15.Li, Y*., Cockburn, W., Kilpatrick, J. & Whitelam, G. C. (2000). Cytoplasmic expression of a soluble synthetic mammalian metallothionein-alpha domain in Escherichia coli. Enhanced tolerance and accumulation of cadmium. Mol Biotechnol 16, 211-9. （* corresponding author）

16.Li, Y*., Cockburn, W., Kilpatrick, J. & Whitelam, G. C. (1999). Selection of rabbit single-chain Fv fragments against the herbicide atrazine using a new phage display system. Food and Agricultural Immunology 11, 5-17. （* corresponding author）

17.Gough, K. C., Li, Y., Vaughan, T. J., Williams, A. J., Cockburn, W. & Whitelam, G. C. (1999). Selection of phage antibodies to surface epitopes of Phytophthora infestans. J Immunol Methods 228, 97-108.

18.Li, Y*., Cockburn, W. & Whitelam, G. C. (1998). Filamentous bacteriophage display of a bifunctional protein A:scFv fusion. Mol Biotechnol 9, 187-93. （*corresponding author）

19. Li, Y., Owen, M. R., Cockburn, W., Kumagai, I. & Whitelam, G. C. (1996). Study of antibody-antigen interaction through site-directed mutagenesis of the VH region of a hybrid phage-antibody fragment. Protein Eng 9, 1211-7.

Book chaptor

1.Gough, K. C., Li, Y. & Whitelam, G. C., in　 edited by. vol. (2002). Antibody Phage Display Libraries. In Molecular plant biology: A practical approach (Gilmartin, P., ed.), Vol. 2, pp. 221-236. Oxford University Press.

Patents(PCT)

1. Jakobsen, BK; Li Y; Moysey, RK. (2008) ILT-2 (LIR1) Variants with increased affinity for MHC calss I moledules, WO 2008/062147

2.Jakobsen, BK; Li Y; Moysey, RK. (2008) Polypeptide monomers and dimmers containing mutated ILT, WO 2008/062158.

3.Jakobsen, BK; Li, Y; Moysey, RK. (2006) Polypeptides, WO 2006/125963.

4.Jakobsen, BK; Li, Y. (2006) T cell receptors which specifically bind to VYGFVRACL-HLA-A24, WO 2006/125962.

5.Jakobsen, BK; Li, Y; Dunn, SM; Molloy, PE. (2006) High affinity HIV T cell receptors. WO 2006/103429.

6.Boulter, JM; Jakobsen, BK; Li, Y; Molloy, PE; Dunn, SM. (2005) Method for the identification of a polypeptide which binds to a geven pMHC complex, WO 2005/116646.

7.Jakobsen, BK; Li, Y. (2005) High affinity telomerase T cell receptors, WO 2005/116075.

8.Boulter, JM; Andersen, TB; Jakobsen, BK; Molloy, PE; Li, Y. (2005) Nucleoproteins Displaying Native T cell receptor libraries, WO 2005/116074.

9.Boulter, JM; Jakobsen, BK; Li, Y; Molloy, PE; Dunn, SM. (2005) High affinity NY-ESO T cell receptors, WO 2005/113595.

10.Jakobsen, BK; Andersen, TB; Molloy, PE; Li, Y; Boulter, JM. (2004) T cell receptor display, WO 2004/044004.

Research: