First publications describing the SHAL platform and the selectivity and high affinity of the first set of SHALs designed to target and bind to non-Hodgkin’s lymphoma cells and tumor biopsy samples:
R. Balhorn, J. Perkins, P.A. Burke, F.C. Lightstone, M. Cosman (Balhorn), C. Venclovas, M. Corzett, S.J. DeNardo, T.A. Lehner, J.P. Gregg., H. Albrecht and G.L. DeNardo. Development of synthetic high affinity ligands that bind to a structural epitope on the tumor cell receptor HLA-DR10. Proc Amer Assoc Cancer Res, Volume 46, (2005)
Balhorn, R., Hok, S., Burke, P.A., Lightstone, F.C., Cosman (Balhorn), M., Zemla, A., Mirick, G., Perkins, J., Natarajan, A., Corzett, M., DeNardo, S.J., Lehner, T.A., Albrecht, H., Gregg, J.P. and DeNardo, G.L. Selective High Affinity Ligand (SHAL) “Antibody Mimics” for Cancer Diagnosis and Therapy: Initial Application to Lymphoma and Leukemia. Clinical Cancer Research 13: 5621-8 (2007).
Describes how the SHALs are synthesized, the efficiencies of the chemical reactions, the yields of product and how they are tagged with radioactive compounds:
Hok, S., Natarajan, A., Balhorn, R., DeNardo, S.J., DeNardo, G.L. and Perkins, J. Synthesis and Radiolabeling of Selective High Affinity Ligands Designed to Target Non-Hodgkin’s Lymphoma and Leukemia. Bioconjugate Chemistry 18: 912-21 (2007).
Describes the production of a recombinant form of the HLA-DR10 protein we can use to test how well the SHALs bind:
Albrecht, H., Cosman (Balhorn), M., Ngu-Schwemlein, Corzett, M., Curran, K.W., Dolan, C., Fang, X., DeNardo, S.J., DeNardo, G.L. and Balhorn, R. Recombinant Expression of the b-subunit of HLA-DR10 for the Selection of Novel Lymphoma Targeting Molecules. Cancer Biotherapy and Radiopharmaceuticals 22: 531-542 (2007).
Compares how a series of first “bidentate” SHALs (molecules containing two binding components) are taken up and distributed in the blood and different organs in mice bearing a human lymphoma tumor following the injection of the SHAL drugs:
DeNardo, G.L, Natarajan, A., Hok, S., Perkins, J., Cosman (Balhorn), M., DeNardo, S.J., Lightstone, F.C., Mirick, G., Miers, L.A. and Balhorn, R. Pharmacokinetic Characterization in Xenografted Mice of a Series of First Generation Mimics for HLA-DR Antibody, Lym-1, as Carrier Molecules to Image and Treat Lymphoma. Journal of Nuclear Medicine 48: 1338-47 (2007).
Describes how a series of “bis-bidentate” SHALs (molecules made up of two SHALs linked together) are taken up and distributed in the blood and different organs in mice bearing a human lymphoma tumor following the injection of the SHAL drugs:
DeNardo, G.L, Hok, S., DeNardo, Cosman (Balhorn), M., S.J., Hoye, E., Lehmann, J., Lightstone, F., Miers, L.A., Mirick, G., Natarajan, A., Sysko, V.V., Xiong, C.-Y. and Balhorn, R. Characteristics of dimeric (bis) bidentate selective High Affinity Ligands (SHALs) as HLA-DR10 Beta-Antibody Mimics to Target non-Hodgkin’s lymphoma (NHL). International Journal of Oncology 31: 729-740 (2007).
Describes the prospects of using radiolabeled antibodies and SHALs to treat/cure lymphoma:
DeNardo, G.L., DeNardo, S.J., and Balhorn, R. Systemic Radiotherapy can cure Lymphoma: A Paradigm for Other Malignancies? Cancer Biotherapy and Radiopharmaceuticals 23: 383-97 (2008).
Comparison of the properties of a number of different SHALs that were synthesized as potential drugs for treating non-Hodgkin’s lymphoma and the discovery that SHALs containing a new ligand (Ct) are toxic to tumor cells in culture:
DeNardo, G., Natarajan, A., Hok, S., Mirick, G., DeNardo, S., Corzett, M., Sysko, V., Lehmann, J., Beckett, L, and Balhorn, R. Nanomolecular HLA-DR10 Antibody Mimics: A Potent System for Molecular Targeted Therapy and Imaging. Cancer Biotherapy and Radiopharmaceuticals 23: 783-795 (2008).
First report showing how the SH7139 cures mice bearing human non-Hodgkin’s lymphoma tumors:
DeNardo, G.L., Mirick, G.R., Hok, S., DeNardo, S.J., Beckett, L.A., Adamson, G.N. and Balhorn, R. Molecular Specific and Cell Selective Cytotoxicity Induced by a Novel Synthetic HLA-DR Antibody Mimic for Lymphoma and Leukemia. International Journal of Oncology 34: 511-516 (2009).
Shows how a small arginine peptide tag can be added to a SHAL and improve its uptake into cells:
Balhorn, R., Hok, S., DeNardo, S.J., Natarajan, A., Mirick, G., Corzett, M. and DeNardo, G.L. Hexa-arginine Mediated Transport of Selective High Affinity Ligands (SHALs) into HLA-DR10 Expressing Cells. Molecular Cancer. 2009 Apr 22; 8:25 (2009).
Shows that SH7139 also binds to dog lymphoma cells and that a biotinylated form of the SHAL can be used as a diagnostic to determine if a certain type of lymphoma is present:
Balhorn, R.L., Skorupski, K.A., Hok, S., Balhorn, M. (Cosman), Guerrero, T., Rebhun, R.B. A Selective High Affinity Ligand (SHAL) Designed to Bind to an Over-expressed Human Antigen on Non-Hodgkin’s Lymphoma also Binds to Canine B-cell Lymphomas. Vet Immunol Immunopathol. 2010 Oct 15;137(3-4):235-42. doi: 10.1016/j.vetimm.2010.05.014. Epub 2010 Jun 2 (2010).
Ga-68 SHAL is listed as one of the diagnostic radiopharmaceuticals under going testing at the Bad Berka neuroendocrine tumor and THERANOSTICS center as part of a “first in man” study.
RP Baum and HR Kulkarni, THERANOSTICS: From Molecular Imaging Using Ga-68 Labeled Tracers and PET/CT to Personalized Radionuclide Therapy – The Bad Berka Experience, Theranostics ; 2(5):437-447. doi: 10.7150/thno.3645 (2012).
Describes the use of a biotinylated version of SH7139 (SH7129) for use as a companion diagnostic
R. Balhorn, R.B. Rebhun, S. Hok, R. Baum, J. Sanger and M.(Cosman) Balhorn. Biotinylated derivatives of selective high affinity ligand (SHAL) therapeutics as companion diagnostics for prescreening non-Hodgkin’s lymphoma patients. Cancer Res ;72(8 Suppl): 4591. doi:1538-7445.AM2012-4591 (2012).
Invited book chapter describing the new types of therapeutics called SHALs and how they can be used also as imaging agents to visualize lymphoma in the body:
R. Balhorn and M. (Cosman) Balhorn Selective High Affinity Ligands (SHALs): A New Class of Targeting Agents for Cancer Imaging and Therapy. In: Medical Radiology, Radiation Oncology, Volume Therapeutic Nuclear Medicine, R.P. Baum, ed., Springer-Verlag, Germany, pp. 139-150 (2014).
R. Balhorn, S. Hok, M. (Cosman) Balhorn. Pilot toxicology study of the B-cell lymphoma drug candidate SH7139 demonstrates lack of toxicity in beagles. Cancer Res ;73(8 Suppl): 4419. doi:10.1158/1538-7445.AM2013-4419 (2013).
R. Balhorn, S. Hok, R. Balhorn. Optimizing a modular synthetic approach for producing SH7139, a new drug candidate for treating B-cell lymphomas. Cancer Res ;73(8 Suppl): 2453. doi:10.1158/1538-7445.AM2013-2453 (2013).
R. Balhorn, G. Mirick, G. L. DeNardo, L. Beckett, J. Li, S. Hok, and M. (Cosman) Balhorn, Effect of route and dosing regimen on efficacy of SH7139 in mouse Burkitt’s lymphoma xenografts. Cancer Res 74:2703 ; doi:10.1158/1538-7445 (2014).
M. (Cosman) Balhorn, G. Mirick, D. Cheng, Z. Ma, E. Y. Lau, S. Hok, G. L. DeNardo, and R. Balhorn, Intracellular uptake and metabolism of SH7139: Is it a targeted prodrug for B-cell lymphomas. Cancer Res 74:5460 ; doi:10.1158/1538-7445 (2014).
M. (Cosman) Balhorn, S. Hok, and R. Balhorn. Multiple mechanisms of action may contribute to the lymphoma cell-killing activity of SH7139. Cancer Res 75: 5498 (2015); doi:10.1158/1538-7445. AM2015-5498.
R. Balhorn, S.Hok and M. (Cosman) Balhorn. Physical and metabolic stability of SH7139, a new drug candidate for non-Hodgkin;s lymphoma targeting HLA-DR10. Cancer Res 75: 4494 ; doi:10.1158/1538-7445. AM2015-4494 (2015).
M. (Cosman) Balhorn and R. Balhorn. Metabolism studies of SH7139, a small molecule drug targeting B-cell malignancies overexpressing HLA-DR10, confirm its prodrug function. Cancer Res ;76(14 Suppl): 1305. doi: 10.1158/1538-7445.AM2016-1305 (2016)
R. Balhorn, A.J. van Adrichem, S. Hok, M. (Cosman) Balhorn. Inhibition of Rac1 GTPase activity by SH7139, a new drug candidate for non-Hodgkin’s lymphoma targeting HLA-DR10. Cancer Res ;76(14 Suppl): 2991. doi:10.1158/1538-7445.AM2016-2991 (2016).
M. (Cosman) Balhorn and R. Balhorn. Therapeutic applications of the selective high affinity ligand drug SH7139 may extend beyond NHL to many other types of solid tumors. Cancer Res 2017: 77, in press.
R. Balhorn, M. (Cosman) Balhorn. Pre-clinical toxicology and safety of SH7139, the first of a new class of targeted therapeutics for non-Hodgkin’s lymphoma and other cancers. Cancer Res 2017:77, in press.