Abstract 1171: Therapeutic applications of the selective high affinity ligand SH7139 may extend beyond NHL to many other types of solid tumors

Abstract

Abstract SH7139, the first of a new class of cancer therapeutics developed for treating non-Hodgkin’s lymphoma, is unusual in that both targeting and pro-drug functionalities have been incorporated into the same small molecule. Functioning similar to an antibody-drug conjugate, SH7139 targets a unique structural epitope within the antigen-binding pocket of HLA-DR10. HLA-DRs containing this epitope within the β-subunit are reported to be over-expressed in approximately 85% of B-cell lymphomas. Upon binding to HLA-DR molecules located on the tumor cell’s surface, SH7139 is transported into the cytoplasm where it is concentrated and subsequently metabolized. A series of metabolic products derived from the SHAL’s recognition elements (three small molecules that are linked together to create SH7139 and to provide targeting selectivity) are generated as the drug is broken down, each of which inhibits one or more activities required for tumor cell survival. Preclinical studies with SH739 have demonstrated remarkable efficacy in treating B-cell lymphoma xenografts in mice, providing permanent cures for up to two-thirds of the animals at a human equivalent dose as low as 0.41 μg/kg. Biopsy tissue binding studies conducted with SH7129, a biotinylated form of SH7139, and streptavidin-horse radish peroxidase detection have shown the drug binds to a significant fraction of tumors obtained from patients diagnosed with multiple myeloma and each of the B-cell lymphoma subtypes tested to date (DLBC, Burkitt’s, Mantle Cell, Follicular, MALT, and CLL). SH7129 was also observed to bind to tumor biopsies obtained from of a number of patients diagnosed with peripheral T-cell and nodular sclerosis Hodgkin’s lymphomas, a result consistent with observations reported by others that HLA-DRs are expressed in a subset of these lymphomas. HLA-DR expression has also been reported to occur in or be linked to a number of other types of cancer, including melanoma, cervical, ovarian, pancreatic and lung cancers. SH7129 staining of tumor microarrays have shown biopsy cores from a subset of patients diagnosed with each of these cancers also bind SH7139. While in vivo efficacy has only been tested in Burkitt’s (Raji), Mantle cell (Granta-519), and T-cell (Jurkat, a cell line control lacking HLA-DR and showing no efficacy) lymphoma xenografts, these tissue binding results suggest that in addition to the majority of the NHL subtypes, nodular sclerosis Hodgkin’s lymphoma, multiple myelomas, as well as a subset of melanomas, ovarian, cervical, pancreatic, and lung cancers may also respond to SH7139 therapy. This research was supported by the National Cancer Institute Phase II SBIR Award R44CA159843. Citation Format: Monique Cosman Balhorn, Rod Balhorn. Therapeutic applications of the selective high affinity ligand SH7139 may extend beyond NHL to many other types of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1171. doi:10.1158/1538-7445.AM2017-1171