Key words: Ovarian cancer, innate immunity, macrophages, complement, mouse models, recombinant antibodies, yeast-display scFv, biobodies, nanoparticles, targeted-imaging and targeted-therapy.

Research Interests:
Our laboratory has two main poles of interest. One is to study the role of the innate immunity in gynecological cancers and the other is to develop new affinity reagents for early diagnostic and therapy of cancer.
 
Role of the innate immunity in gynecological cancers
We hypothesized that GPI-anchored tumor antigens play a functional role in tumor development and we are currently dissecting their involvement in the phenotype switch of tumor-associated macrophages. We are also exploring the roles of various complement factors in tumor growth, using novel mouse models, complement inhibitors and glycosyltransferase mirRNA inhibitors.
 
Development of new affinity reagents for early diagnostic, targeted-imaging and -therapy of ovarian cancer
The Scholler laboratory develops affinity reagents directed against macrophage receptors, tumor antigens and tumor vasculature markers using novel yeast-display and yeast-expression systems. We developed a system of expression in yeast to produce soluble, directly biotinylated recombinant proteins. In vivo biotinylation of the yeast-secreted proteins is achieved by a biotin ligase produced by the yeast mating partner and directed to the yeast secreting compartment via KEX sequences. In vivo biotinylation specifically arises on a biotin accepting site fused to the secreted protein or scFv, in frame with an IgA hinge in C- or N-terminal. Because the BCCP is distant from the scFv, conformational alterations during antigen-independent binding become negligible, which preserves scFv antigen-specific binding. These novel recombinant antibodies, called biobodies, were successfully used as affinity reagents for diagnostic assays, cellular functional assays and in novel discovery platforms. Biobodies can easily be covalently coupled to labeled and/or immobilized streptavidin, allowing the generation of biobody-targeted nanoparticles for imaging and therapy.
 
Research Techniques:
In vivo models of ovarian cancers, construction and screening of yeast-display scFv libraries, yeast expression of in vivo biotinylated proteins, mammalian expression of recombinant proteins, magnetic and flow sortings, targeted-nanoparticles, molecular biology, biochemistry, immunohistochemistry, in vitro culture and maturation of human macrophages.
Publications:
Lowe K., Shah C., Wallace E., Anderson G., Paley P., McIntosh M., Andersen R., Scholler N., Bergan L., Thorpe J., Urban N., Drescher C. Effects of personal characteristics on serum CA125, mesothelin, and HE4 levels in healthy post-menopausal women at high-risk for ovarian cancer. Cancer Epidemiology, Biomarkers & Prevention. In press.

Scholler N., Gross J.A., Garvik B., Wells L., Liu Y., Loch C.M., Ramirez A.B., McIntosh MW., Lampe P.D., Urban N. Use of cancer-specific yeast-secreted in vivo biotinylated recombinant antibodies for serum biomarker discovery. Journal of Translational Medicine. 2008, 6:41.

Andersen M.R., Goff B.A., Lowe K.A., Scholler N., Bergan L., Dresher C.W., Paley P., Urban N. Combining a symptoms index with CA 125 to improve detection of ovarian cancer. Cancer. 2008 Jun 25. Jun 25;113(3):484-489. DOI: 10.1002/cncr.23577.

Palmer C., Duan X., Hawley S., Scholler N., Thorpe J., Sahota R., Wong M., Wray A., Drescher C., McIntosh M., Brown P., Nelson B., Urban N.  Systematic evaluation of candidate blood markers for detecting ovarian cancer. PLoS ONE - 2008 Jul 9;3(7):e2633.

Faca, V., Song, K., Wang, H., Zhang, Q., Krasnoselsky, A., Ireton, R., Newcomb, L., Plentz, R., Glukhova, V., Phanstiel, D., Gurumurthy, S., Redston, M. S., Brenner, D., Anderson, M., Misek, D., Scholler, N., Urban, N., Barnett, M., Edelstein, C., Goodman, G., Thornquist, M., McIntosh, M., DePinho, R. A., Bardeesy, N. and Hanash S. Markers for human pancreatic cancer based on plasma proteome analysis of a mouse model. PLoS Med. 2008 Jun 10;5(6):e123.

Scholler, N., Lowe, K. A., Bergan, L. A., Kampani, A. V., Ng, V., Forrest, R. M., Thorpe, J. D.,  Gross, J. A., Garvik, B. M., Drapkin, R., Anderson, G. L. and Urban, N. Use of yeast-secreted in vivo biotinylated recombinant antibodies (biobodies) in bead–based ELISA. Clinical Cancer Research. 2008 May 1:14(9):2647-55.

Loch, C. M., Ramirez, A. B., Liu, Y., Sather, C. L., Delrow, J.J., Garvik, B., Scholler, N., Urban, N., McIntosh, M. W. and Lampe, P. D.  Use of high density antibody arrays to validate and discover cancer serum biomarkers. Molecular Oncology. Volume 1, Issue 3, December 2007, Pages 313-320.

Scholler, N., Garvik, B., Hayden-Ledbetter, M., Kline, T., and Urban, N. . Development of a CA125-mesothelin cell adhesion assay as a screening tool for biologics discovery. Cancer Lett. 2007. 247, 130-6.

Bergan, L., Gross, J. A., Nevin, B., Urban, N., and Scholler, N. 2007. Development and in vitro validation of anti-mesothelin biobodies that prevent CA125/Mesothelin-dependent cell attachment. Cancer Lett 255, 263-74.

Scholler, N., Crawford, M., Sato, A., Drescher, C. W., O'Briant, K. C., Kiviat, N., Anderson, G. L., and Urban, N. (2006). Bead-based ELISA for validation of ovarian cancer early detection markers. Clin Cancer Res 12, 2117-24.

Scholler, N., Garvik, B., Quarles, T., Jiang, S., and Urban, N. 2006. Method for generation of in vivo biotinylated recombinant antibodies by yeast mating. J. Immunol Methods. 2006. 317, 132-43.

McIntosh, M. W., Drescher, C., Karlan, B., Scholler, N., Urban, N., Hellstrom, K. E., and Hellstrom, I. (2004). Combining CA 125 and SMR serum markers for diagnosis and early detection of ovarian carcinoma. Gynecol Oncol 95, 9-15.

Disis, M. L., Scholler, N., Dahlin, A., Pullman, J., Knutson, K. L., Hellstrom, K. E., and Hellstrom, I. (2003). Plasmid-based vaccines encoding rat neu and immune stimulatory molecules can elicit rat neu-specific immunity. Mol Cancer Ther 2, 995-1002.

Scholler, N., Hayden-Ledbetter, M., Dahlin, A., Hellström, I., Hellström, K. E. and Ledbetter, J. A. 2002. CD83 Regulates the Development of Cellular Immunity. Journal of Immunology. 168: 2599-2602.

Scholler, N., Hayden-Ledbetter, M., Hellström, I., Hellström, K. E. and Ledbetter, J. A. 2001. CD83 is a Sialic Acid-Binding Immunoglobin-Like Lectin (Siglec) Adhesion Receptor that Binds Monocytes and a Subset of Activated CD8+ T Cells. Journal of Immunology. 166: 3865-3872.

Scholler, N., Disis, M. L., Dahlin, A., Hellström, K. E., Pullman, J. and Hellström, I. 2001. HER2 DNA immunization with costimulatory molecules elicits functional anti-HER2 antibodies. Molecular Therapy. 3(5): S69-70.

Hellström, I., Ledbetter, J. A., Scholler, N., Yang, Y., Ye, Z. M., Goodman, G. E., Pullman, J., Hayden-Ledbetter, M. and Hellström, K. E. 2001. CD3-mediated activation of tumor-reactive lymphocytes from patients with advanced cancer. Proceedings of the National Academy of Sciences of the United States of America. Jun 5; 98(12): 6783-6788.

Scholler, N., Fu, N., Yang, Y., Ye, Z. M., Goodman, G. E., Hellström, K. E. and Hellström, I. 1999. Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. Proceedings of the National Academy of Sciences of the United States of America. 96(20):11531-11536.

Couissiner-Paris, P., Bourgeois, A., Nessein, H., Bacellar, O., Rodriguez, V. Jr., Kohlstadt, S., Buonavista, N., Pene, J. and Dessein, A. J. 1995. Identification of a major T cell immunogen in the anti-schistosome response of adult residents in an area endemic of Schistosoma mansoni. European Journal of Immunology. 24 (4): 903-910.

Cornillon, S., Foa, C., Davoust, J., Buonavista, N., Gross, J. D. and Goldstein, P. 1994. Programmed cell death in Dictyostelium. Journal of Cell Science. Oct; 107(10): 2691-2704.

Balzano, C., Buonavista, N., Rouvier, E. and Goldstein, P. 1992. CTLA-4 CD28, similar protein, neighboring genes. International Journal of Cancer. Suppl 7, 28-32.

Buonavista, N., Balzano, C., Pontarotti, P., Le Paslier, D. and Goldstein, P. 1992. Molecular linkage of human CTLA-4 and CD28 Ig-superfamily genes in yeast artificial chromosomes. Genomics. Jul; 13(3):856-861.