The goal of this SBIR proposal is to complete the majority of the pre-clinical studies and testing needed to submit an IND application and advance a promising new therapeutic for non- Hodgkin's lymphoma, SH7139, into a clinical trial. SH7139 is a selective, high affinity ligand (SHAL) that was designed to target a unique site on HLA-DR10, a protein receptor found on the surface of B-cell lymphocytes and overexpressed in many B-cell derived lymphomas and leukemias. SH7139 binds selectively and is highly cytotoxic (at pM concentrations) only to tumor cells expressing HLA-DR10. In a Raji xenograft mouse model, 69% of animals treated with 5?g/kg of SH7139 experienced a permanent cure;that is, the tumors disappeared within 30 days after treatment and did not return during the remainder of the life of the animal. In addition, no adverse side effects have been observed in animals, even when the dose was increased 2000-fold.
The specific aims proposed in phase II of this SBIR are to: (1) determine the potential impact of SH7139 metabolism and metabolites on its function and the metabolism of other drugs;(2) confirm the mechanism of action of SH7139;(3) determine the pharmacokinetics, toxicology and safety of SH7139 in rodents and dogs;and (4) confirm SH7139 selectivity for B-cell malignancies and identify the potential breadth of the SH7139 indication. Upon the successful completion of this Phase II project, SHAL Technologies will use the results to identify any additional tests that need to be conducted, prepare and submit an IND application, open a Phase I clinical trial, and move forward with the clinical evaluation of SH7139 as a new therapeutic for treating and potentially curing advanced non-Hodgkin's lymphoma and other B-cell derived forms of cancer. If successful, this effort will provide a more effective first-line therapy for advanced NHL. Fewer side effects would be expected, because only those cells that are overexpressing HLA-DR10 are targeted and killed;normal cells are not affected. SH7129, a biotinylated analog of SH7139, could be used as companion diagnostic to identify those patients for whom this treatment would be most likely to be effective. Radionuclide-tagged SH7139 may also prove useful as an imaging agent to monitor the progression of the patient's disease. The low cost of SH7139 synthesis should reduce the cost of NHL therapy significantly and make the drug available to all those diagnosed with NHL.
There is a public health need to develop more efficacious, less toxic and more cost effective treatments for advanced cancers. This project addresses this need by proposing the studies and testing that must be completed to advance into clinical trials a promising new targeting agent and therapeutic for patients with non-Hodgkin's lymphoma, which our current results suggest is remarkable and is likely to improve patient survival and reduce side effects and treatment costs significantly.