1982-1985: B.Sc in biology, Tel Aviv University, Israel
1987-1988: M.Sc. in animal sciences Cum Laude. Hebrew University of Jerusalem, Israel
1991-1994: D.Sc. in comparative immunology. Technion - Israel Institute of Technology
Postgraduate Education and Training
1994-1995: Evolution of TNF receptors and ligands. Weizmann Institute of Science, Israel
1995-1996: Sponge and tunicate immune related molecules. Mainz University, Germany
1997-2001: Sea urchin immunity. California Institute of Technology
2002-2005: Origin of adaptive immunity. University of Alabama at Birmingham
I. Unique biomedicine-important antibodies from ancient fish
We discovered the unique antibodies derived from jawless fish (lamprey and hagfish) which are representatives of the oldest vertebrate taxon and have biomedical importance. We call these antibodies variable lymphocyte receptors (VLR) as they are uniquely built from hypervariable leucine-rich repeats. This structure of antibodies is unique and is distinct as compared to antibodies of all jawed vertebrates (from shark to man) which consist of immunoglobulins. VLRs can target diverse antigens as the number of potential unique receptors is comparable to that of the human antibodies and T-cell receptors.
We study the antigen binding properties of VLRs that are recombinantly expressed in yeast and are developing this system to produce reagents for the analysis of human disease states. To achieve this, we developed a high-throughput method to isolate antigen-specific binding VLR clones using yeast surface display. We have isolated reagents for detection of protein and carbohydrate antigens having affinities comparable to the best conventional mammalian antibodies. Structural studies on VLR complexed with their cognate antigens indicate VLRs are highly stable single-chain proteins that can be easily modified by random and targeted mutagenesis to improve binding to antigen. In this way VLRs can thus be engineered as superior alternatives to conventional antibodies for biomedical and therapeutic application.
We are currently developing VLR-binders for tumor specific glycan antigens. Most cancer cells express hyperglycosylated surface glycoproteins that carry aberrant or unique glycans, which frequently mask/shield the tumor from the immune system because glycans are poorly immunogenic for conventional antibodies. VLRs can bind many of these glycans with high affinity and specificity and our goal is to engineer VLRs for highly sensitive detection and targeting of cancer cells. We are also interested in other antigens that are poorly immunogenic for conventional antibodies, for example due to tolerance of the mammalian immune system to self-antigens.
II. Synthetic biology
We are also working to create a “synthetic immune system” by grafting to yeast the essential components of adaptive immunity. An adaptive immune system consists of three basic elements: 1) a large population of proliferation competent cells, each expressing a unique surface receptor, 2) clonal expansion of selected cells in response to antigen binding and, 3) affinity maturation to improve binding to antigen. Using the VLR as antigen binding receptors we are engineering yeast with an artificial adaptive immune system. When complete, this system can be used for automated, cost-effective, high-throughput production of superior immunological reagents. Furthermore, we hope that studying this simple “synthetic immune system” can teach us much about the adaptations that are required for an organism to acquire a complex adaptive immune system, and that this will provide insights regarding function of the human immune system.
Pancer, Z., Amemiya, C.T., Ehrhardt, G.R.A., Ceitlin, J., Gartland, G.L. and Cooper, M.D. (2004) Somatic diversification of variable lymphocyte receptors in the agnathan sea lamprey. Nature 430:174-80.
Alder, M.N., Rogozin, I.B., Iyer, L.M., Glazko, G.V., Cooper, M.D. and Pancer, Z. (2005) Diversity and function of adaptive immune receptors in a jawless vertebrate. Science 310:1970-3.
Rogozin, I.B, Iyer, L.M., Liang, L., Glazko, G.V., Liston, V.G., Pavlov, Y.I., Aravind, L. and Pancer, Z. (2007) Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nature Immunology 8:647-56.
Velikovsky, C.A., Deng, L., Tasumi, S., Iyer, M.L., Kerzic, M.C., Aravind, L., Pancer, Z. & Mariuzza, R.A. (2009) Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen. Nat. Struc. Mol. Biol. 16:725-30.
Tasumi, S., Velikovsky, C.A., Xu, G., Gai, S.A. Wittrup, K.D., Flajnik, M.F., Mariuzza, R.A. & Pancer, Z. (2009) High-affinity lamprey VLRA and VLRB monoclonal antibodies. Proc. Natl. Acad. Sci. USA 106:12891-6.