Immunotherapy of cancer, viral infection and autoimmune disease

1992-1995 Ph. D. School of Biological Sciences, University of Leicester, UK.
Thesis: Antibody Engineering Studies Using Filamentous Bacteriophage Display Technology.
1982 - 1987 M.B. Faculty of Medicine, Hunan Medical University, China.

2012-Present Principal Investigator, GuangZhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
2011-2012 Director, Protein Technology, Immunocore Ltd, Oxford, UK
2003-2011 Head, Protein Engineering, Avidex/Immunocore Ltd, Oxford, UK
2002-2003 Senior Scientist, Phage Display, Avidex Ltd, Oxford, UK
2000-2002 Research Manager, Biovation Ltd / Merck KgaA
2000-2000 Senior Research Scientist, ADAS Ltd, Hereford, UK
1996-2000 Research Scientist, ADAS Ltd, Hereford , UK
1995-1996 Postdoctoral Molecular Immunologist, ADAS Ltd, Hereford , UK
1992-1995 Research Assistant, Department of Biology, University of Leicester, UK.
1991-1992 Research Assistant, Department of Biochemistry, Medical School, University of Manchester, and Department of Immunology, St. Mary’s Hospital, Manchester, UK
1987-1991 Physician/ Research Assistant China Leprosy Control and Research Centre / Guangdon Dermatosis Center, Guangzhou, China.

1. Zhang H, Zhang J, Chen L, Weng Z, Tian Y, Zhao H, Li Y, Chen L, Liang Z, Zheng H, Zhao W, Zhong S, Li Y. (2016) Targeting naturally occurring epitope variants of hepatitis C virus with high-affinity T-cell receptors. J Gen Virol. Nov 11. doi: 10.1099/jgv.0.000656. [Epub ahead of print]

2. 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. NatureMedicine 18(6), 980-7 (Author Contributions N.L., N.E.H., P.E.M. and E.G. isolatedwildtype mTCRs and carried out the phage display process under the supervision of Y.L.;A.V. and Y.L. were involved in ImmTAC construct optimisation; et al)

3. Cole DK1, Miles KM, Madura F, Holland CJ, Schauenburg AJ, Godkin AJ, Bulek AM, Fuller A, Akpovwa HJ, Pymm PG, Liddy N, Sami M, Li Y, Rizkallah PJ, Jakobsen BK, Sewell AK (2014) T-cell receptor (TCR)-peptide specificity overrides affinity-enhancing TCR-major histocompatibility complex interactions. J Biol Chem. 289, 628-638.

4. Cole DK, Sami M, Scott DR, Rizkallah PJ, Borbulevych OY, Todorov PT, Moysey RK, Jakobsen BK, Boulter JM, Baker BM, Yi Li. (2013) Increased Peptide Contacts Govern High Affinity Binding of a Modified TCR Whilst Maintaining a Native pMHC Docking Mode. Front Immunol. 4, 168-175

5.  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

6. 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

7. 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 highaffinity T-cell receptor. Mol Cancer Ther. 6: 2081-91 (*.co-first author).

Apply for more than 30 patents, most of which will be excellence targets to tumor and autoimmune disease virus in future.

The major research interest of Dr Li’s group 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 unmet medical needs. 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 thymus, naturally isolated soluble wild-type TCRs are very low affinity binding protein against the targets and therefore unsuitable for targeting therapeutic usages. The HAT is generated from the naturally isolated low affinity TCR after increasing its affinity over million fold by directed molecular evolution. In order to redirect the patients CTLs against targeted diseased cells, we fuse an anti-CD3 scFv to the HATs to create bi-functional proteins of High Affinity T-cell activation core（HATac）. The HATac will guide highly specific and potent CTL response, leading to CTL mediated destruction of target cells presenting very low copies of peptide-MHC complex.

The second research interest is to investigate the structural mechanisms 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 tumour 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 alternation in the peripheral environment after the V(D)J gene arrangement and positive/negative selection in the thymus, but there are huge number of antigens could be seen by T cell. So according to the rule of one T cell for one antigen, the total number of T cells is limited and less than the amount of antigens that should be recognized by T cells. What is the mechanism that the over numbered antigens could be recognized by limited number of T cells? We postulate the structural plasticity of TCR is the most likely answer for this question. Such researches will shed light on fundamental immunological conundrums and providing valuable information to design better strategies for immunotherapy.

Graduate students

Qiang Liu  02  63228  

Undergraduate students

Siqi Peng  02  19183  

Junnan Lu  01  19183  

Yajing Zhang  02  19183  

Lin Chen  01  19183  

Qi Liu  01  19183