Identifying and validating novel therapeutic targets and biomarkers by in-depth mechanistic study of pathological diseases. Functional Monoclonal Antibodies (mAb) to these specific targets will be developed for potential application in diagnosis and treatment. We are particularly interested in the following areas:
- Cancer immunotherapy. Tumor cells can evade T-cell immune surveillance through several escape mechanisms, such as defective recognition of tumors by activated T cells, induction of anergy in activated T cells and tumor cell “counter attack” etc. We will explore the manifold interactions between tumors and T cells to improve T-cell-based immunotherapy strategies. To restore an effective T-cell-mediated antitumor response in patients, we will develop antibodies against specific immunosuppressive molecules that impair T-cell function or lead to T-cell anergy and/or apoptosis. We will also make T Cell-Engaging Bi-Specific antibodies binding to tumor antigens to promote T cell-dependent direct tumor killing.
- (Infectious diseases, such as Influenza and other viral infections, can potentially be effectively treated with antibody drugs. Antibodies selected from immune samples have been demonstrated to have high specificity and affinity for the antigens due to their extensive somatic hypermutation. Immune phage libraries generated from those virus-infected human patients will enable identification of potent therapeutic antibodies from disease survivors.
- Establishing following State-Of-The-Art antibody discovery platforms and antibody engineering technologies that enable us select mAb with high affinity and desired function: (1) Phage display technologies; (2) Molecular hybridoma technology and humanization by CDR grafting; (2) Fc region engineering; (4) Novel bi-specific antibody generation.
- Developing intracellular mAb (intrabody) against intracellular drug target. Formation and disassembling of signaling complex, such as inflammsome, DISC (Death Inducing Signaling Complex) has an important function in many physiological conditions, and their de-regulation has been observed in many diseases. We are interested in developing scFv or other scaffold proteins that can specifically interfere protein-protein interaction or protein modification by blocking certain epitopes. We can then precisely dissect the role of each molecule and its binding partners in the signaling complex with these tools, and the results will also guide us to validate small molecule targets. More importantly, intrabodies can potentially be developed as therapeutics targeting intracellular oncogenes and tumor suppressor genes if they are combined with gene therapy or improved antibody delivery technologies in future.
1. Misaghi S, Senger K, Sai T, Qu Y, Sun Y, Hamidzadeh K, Nguyen A, Jin Z, Zhou M, Yan D, Lin WY, Lin Z, Lorenzo MN, Sebrell A, Ding J, Xu M, Caplazi P, Austin CD, Balazs M, Roose-Girma M, DeForge L, Warming S, Lee WP, Dixit VM, Zarrin AA. Polyclonal hyper-IgE mouse model reveals mechanistic insights into antibody class switch recombination. Proc Natl Acad Sci U S A. 2013 Sep 24;110(39):15770-5.
2. Hegde GV, de la Cruz CC, Chiu C, Alag N, Schaefer G, Crocker L, Ross S, Goldenberg D, Merchant M, Tien J, Shao L, Roth L, Tsai SP, Stawicki S, Jin Z, Wyatt SK, Carano RA, Zheng Y, Sweet-Cordero EA, Wu Y, Jackson EL. Blocking NRG1 and Other Ligand-Mediated Her4 Signaling Enhances the Magnitude and Duration of the Chemotherapeutic Response of Non-Small Cell Lung Cancer. Sci Transl Med. 2013 Feb 6;5(171).
3. Jin Z. IAP and death receptors-targeted therapies in bladder cancer. Cancer Biol Ther. 2010 Dec 1;10(11):1098-100.
4. Jin Z, Li Y, Pitti R, Lawrence D, Pham V, Lill J, and Ashkenazi A. Cullin3-Based Polyubiquitination and p62-Dependent Aggregation of Caspase-8 Mediate Extrinsic Apoptosis Signaling. Cell. 2009 May;137(4):721-735.
5. Ricci MS, Kim SH, Ogi K, Plastaras JP, Ling J, Wang W, Jin Z, Liu YY, Dicker DT, Chiao PJ, Flaherty KT, Smith CD, El-Deiry WS. Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell. 2007 Jul; 12(1):66-80.
6. Dicker DT, Kim SH, Jin Z, El-Deiry WS. Heterogeneity in non-invasive detection of apoptosis among human tumor cell lines using annexin-V tagged with EGFP or Qdot-705. Cancer Biol Ther. 2005 Sep; 4(9):1014-7.
7. Jin Z, El-Deiry WS. The Distinct Roles of Adaptors and Caspases in Death Receptor-Mediated Apoptosis. Molecular and Cellular Biology. 2006 Nov; 26(2): 8136-8148
8. Jin Z, El-Deiry WS. Overview of cell death signaling pathways. (Review) Cancer Biology and Therapy. 2005 Feb; 4(2):139-63.
9. Ricci MS, Jin Z, Dews M, Yu D, Thomas-Tikhonenko A, Dicker DT and El-Deiry. Direct Repression of FLIP Expression by c-Myc is a Major Determinant of TRAIL Sensitivity. Molecular and Cellular Biology. 2004 Oct; 24(19):8541-55.
10. Jin Z, McDonald III ER, Dicker DT, and El-Deiry WS. Deficient TRAIL Death Receptor Transport to the Cell Surface in Human Colon Cancer Cells Selected for Resistance to TRAIL-Induced Apoptosis. The Journal of Biological Chemistry. 2004 279:35829-39.
11. Jin Z, Dicker DT, El-Deiry WS. Enhanced sensitivity of G1 arrested human cancer cells suggests a novel therapeutic strategy using a combination of simvastatin and TRAIL. Cell Cycle, 2002 1:82-9.
12. Mitchell, K.O., Ricci, S., Miyashita, T., Dicker, D.T., Jin, Z., Reed, J., EL-Deiry, W.S. Bax is a transcriptional target and mediator of c-Myc-induced Apoptosis. Cancer Research, 2000 60: 6318-6325
13. Goldberg GS, Jin Z, Ichikawa H, Naito A, Ohki M, El-Deiry WS, Tsuda H. Global effects of anchorage on gene expression during mammary carcinoma cell growth reveal role of tumor necrosis factor-related apoptosis-inducing ligand in anoikis. Cancer Res. 2001 61:1334-1337
14. Jin Z, Yao HY, Li Z, Rao Y, Ku B. The Distinct Roles of 5HTIA and 5-HT2 Receptors in the modulation of sleep phases. Chinese Pharmacological Bulletin, 2000 16:208-211
15. Jin Z, Yao HY, Li Z, Rao Y, Wang Y, Ku B. The New Automatic System for monitoring andAnalyzing the Sleep Phases of Rat. Chinese Pharmacological Bulletin, 1999 15:411-414