Associate Professor of Pharmaceutics and Pharmaceutical Chemistry
Peptides, Host Immune Systems Peptide Materials
Peptides, including polypeptides, perform versatile and important functions in life. So, it is not a surprise that many new biomaterials were invented using them as building blocks to mimic, refine, enhance, or inhibit their biological functions. Many of these materials are purposely developed as a means to intervene in some important yet abnormal processes in the human body that cause diseases. However, to safely and effectively use these materials in humans, they have to be proved biocompatible. One frequently raised biocompatibility question about peptide materials is whether they are immunogenic. If a peptide material is immunogenic, and its induced immune responses jeopardize its biological functions and the health of its host, its medical applications are doomed to failure.
We are interested in understanding the interplays between exogenous peptides and the host immune systems so that we can apply our understandings to re-engineer known peptide materials and to modulate their immunogenicity without negatively impacting their established functions and properties. We are currently using elastin-like polypeptide or ELP, a popular type of peptide material as our model to carry our studies. Through the studies, we have generated a variant from conventional ELP, namely immunotolerant elastin-like polypeptides (iTEPs). We also hope, through the studies, to answer some fundamental immunogenicity questions shared by peptide material research. One example of such questions is whether different presentations of the same peptide to the immune system result in different immune responses to the peptides? For example, would immune responses be the same to the identical peptide when they are exposed to the immune system as a single molecule or an aggregate?
The second research thrust of our lab concerns medical applications of iTEPs. We are particularly interested in devising iTEP-based nanocarriers for vaccines. Because the sequences and sizes of recombinant iTEPs can be precisely controlled using genetic engineering approaches, we will be able to generate nanocarriers with well-defined sizes, physicochemical properties, and targeting ligands, which allows us to thoroughly investigate factors that may affect the efficacy of vaccine carriers. On the application aspect, because of the broad utilization of vaccines, our iTEP carriers may find applications in treating and preventing a wide spectrum of diseases such as cancer, infection, neurodegeneration, and autoimmunity. The second application focus of iTEPs is to use them deliver small cancer chemotherapeutics. One ongoing project in our lab is to devise iTEP nanoparticles to deliver anti-metastasis drugs to metastasis-initiating cells (MICs) in tumors. Here, we hypothesize that the pinpoint property of iTEP nanocarriers is instrumental for us to control spatial and temporal distributions of the drugs inside tumor tissues so that the drugs may have a better access to MICs than free drugs, which hopefully leads to a better metastasis inhibition outcome.
- Zhai Y, Mossavi R, Chen M (2021). Immune checkpoints, a novel class of therapeutic targets of autoimmune diseases. An invited review for Frontiers in Immunology, section Immunological Tolerance and Regulation. doi: 10.3389/fimmu.2021.645699
- Dong S, Subramanianb S, Parent KN, Chen M (2020) Promotion of CTL epitope presentation by a nanoparticle with environment-responsive stability and phagolysosomal escape capacity. Journal of Controlled Release 328, 653-664
- Zhao P, Wang P, Dong S, He X, Zhou Z, Cao Y, Yagita H, He X, Fisher SJ, Fujinami RS, Chen M (2019). Depletion of PD-1-positive cells ameliorates autoimmune disease. Nature Biomedical Engineering 3, 292-305
- Wang P, Dong S, Zhao P, He X, Chen M (2018). Direct loading of CTL epitopes onto MHC class I complexes on dendritic cell surface in vivo. Biomaterials 182, 92-103.
- Wang P, Zhao P, Dong S, Xu T, He X, Chen M (2018). An albumin binding polypeptide both targets cytotoxic T lymphocyte vaccines to lymph nodes and boosts vaccine presentation by dendritic cells. Theranostics 8(1), 223-236.
- Dong S, Wang P, Zhao P, Chen M (2017). Direct loading of iTEP-delivered CTL epitope onto MHC class I complexes on the dendritic cell surface. Molecular Pharmaceutics 14(10), 3312-3321.
- Dong S, Xu T, Wang P, Zhao P, Chen M (2017). Engineering of a self-adjuvanted iTEP-delivered CTL vaccine. Acta Pharmacologica Sinica 38(6), 914-923
- Zhao P, Atanackovic D, Dong S, Yagita H, He X, Chen M (2017). An anti-programmed death-1 antibody (αPD-1) fusion protein that self-assembles into a multivalent and functional αPD-1 nanoparticle. Molecular Pharmaceutics 14(5), 1494-1500.
- Zhao, P., Xia, G., Dong, S., Jiang, Z.X., and Chen, M. (2016) An iTEP-salinomycin nanoparticle that specifically and effectively inhibits metastases of 4T1 orthotopic breast tumors. Biomaterials 93: 1-9
- Dong, S., Xu, T., Zhao, P., Parent, K.N., and Chen, M. (2016) A Comparison Study of iTEP Nanoparticle-Based CTL Vaccine Carriers Revealed a Surprise Relationship between the Stability and Efficiency of the Carriers. Theranostics 6: 666-78
- Cho, S., Dong, S., Parent, K.N., and Chen, M. (2016) Immune-tolerant elastin-like polypeptides (iTEPs) and their application as CTL vaccine carriers. J Drug Target 24: 328-39
- Mastria, E.M.*, Chen, M.*, McDaniel, J.R., Li, X., Hyun J. Dewhirst M.W., and Chilkoti, A. (2015) Doxorubicin-conjugated polypeptide nanoparticles inhibit metastasis in two murine models of carcinoma.Journal of Controlled Release 208: 52-58 (*Equal contributions)
- Zhan, J., Kale, V., and Chen, M. (2014) Gene Directed Enzyme Prodrug Therapy. American Association of Pharmaceutical Scientists Journal 17: 102-110
- Zhao, P., Dong, S., Bhattacharyya, J., and Chen, M. (2014) iTEP Nanoparticle-Delivered Salinomycin Displays an Enhanced Toxicity to Cancer Stem Cells in Orthotopic Breast Tumors. Molecular Pharmaceutics 11: 2703-12
- Chen, M., McDaniel, J.R., MacKay, J.A., and Chilkoti, A. (2011) Nanoscale self-assembly in delivery of diagnostic or therapeutic agents. Technology and Innovation - Proceedings of the National Academy of Inventors 13: 5-25
- Liu, W., MacKay, J.A., Dreher, M.R., Chen, M., McDaniel, J.R., Simnick, A.J., Callahan, D.J., Zalutsky, M.R., and Chilkoti, A. (2010) Injectable intratumoral depot of thermally responsive polypeptide-radionuclide conjugates delays tumor progression in a mouse model. Journal of Controlled Release 144: 2-9
- MacKay, J.A.*, Chen, M.*, Liu, W., McDaniel, J., Simnick, A., and Chilkoti, A. (2009) Self-assembling chimeric polypeptide-doxorubicin conjugate nanoparticles that abolish tumors after a single injection. Nature Materials 8: 993-999 (*Equal contributions as the first authors)
- Sadegh-Nasseri, S., Chen, M., Narayan, K., and Bouvier, M. (2008) The convergent roles of tapasin and HLA-DM in antigen presentation. Trends in Immunology 29: 141-147
- Chen, M. and Bouvier, M. (2007) Analysis of interactions in a tapasin/class I complex provides a mechanism for peptide selection. EMBO Journal 26: 1681-1690 Recommended as a “Must Read” paper with a F1000 Factor of 6.4 by Faculty of 1000 Biology
- Tan, Y., Chen, M., Li, Z., Mabuchi, K., and Bouvier, M. (2006) The calcium- and zinc-responsive regions of calreticulin reside strictly in the N-/C-domain. Biochimica et Biophysica Acta – General Subject 1760: 745-753
- Chen, M., Stafford, W.F., Diedrich, G., Khan, A., and Bouvier, M. (2002) A characterization of lumenal region of human tapasin reveals the presence of two structural domains. Biochemistry 41: 14539-14545