SBIR-STTR Award

The goal of this SBIR project is to complete the preclinical studies required to submit an IND application for a promising new therapeutic (SH7139) for non-Hodgkin's lymphoma so as to be able to advance this drug into clinical trials. 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. HLA-DR10 is over-expressed 10- 100 fold in many B-cell derived lymphomas and leukemias. The results we obtained from a previously funded NIH/NCI program project grant showed that SH7139 targets the HLA-DR10 receptor with very high affinity (Kd ~ 23 pM) and that it selectively kills only cells over-expressing HLA-DR-10. In a Raji xenograft mouse model, 69% of the animals treated with 55g/kg of SH7139 experienced a permanent cure;that is, the tumors disappeared within 30 days after treatment and did not reoccur during the remainder of the life of the animal. In addition, no adverse side effects were observed in the animals, even when the dose was increased by 2000- fold. The specific aims proposed in Phase I of this SBIR are to: (1) synthesize, chemically characterize and test the biological activity of a SH7139 standard;(2) scale up the synthesis of SH7139 to multi-gram quantities and check its purity, physical characteristics and biological activity against that of the standard compound;and (3) determine the dose of SH7139 that provides the highest cure rate in a xenograft model and use this information to define the doses used in the preclinical, toxicology and safety studies that will be performed in Phase II of the SBIR. Following the completion of the Phase I SBIR study, we will submit a Phase II SBIR proposal in which the scale-up synthesis protocol and dose information obtained in Phase I will be used to produce GMP SH7139 and complete the remaining pre-clinical, toxicology and safety studies that are necessary to submit the IND application. If successful, this effort will develop a more effective first-line therapy for advanced NHL, one that is systemically non-toxic and provides cures rather than incremental increases in the delay of cancer progression. The advantages of SH7139 over the FDA approved NHL drugs and many others in development are: (1) SH7139 represents a dramatic departure from current B-cell lymphoma therapeutics, including Rituxan. In addition to being highly specific in targeting and killing only tumor cells, cures (not complete responses) are achieved in the majority of the treated individuals (mice bearing xenografts), (2) Fewer side effects would be expected, because only those cells that are over-expressing HLA- DR10 are targeted and normal cells are not affected. (3) Because SH7139 is a targeting agent, it can also be used as a companion diagnostic to identify those patients for whom this treatment would be most likely to be effective, thereby minimizing the risks associated with therapy. (4) The low cost of synthesis of this drug should reduce NHL therapy costs significantly, enabling treatments to become more widely available and accessible.

Public Health Relevance:
There is a public health need to develop more efficacious, less toxic and more cost effective treatments for advanced cancers. This project addresses these issues by proposing studies needed to advance into the clinic a promising new targeting agent and therapeutic for patients with advanced Non-Hodgkin's lymphoma, which our preliminary results suggest is remarkable and is likely to improve patient survival and reduce side effects and treatment costs significantly.

Thesaurus Terms:
Address;Advanced Cancer;Advanced Malignant Neoplasm;Adverse Effects;Affect;Affinity;After Care;After-Treatment;Aftercare;Animals;B Blood Cells;B Lymphoma;B-Cell Lymphomas;B-Cells;B-Lymphocytes;Binding;Binding (Molecular Function);Biologic Characteristic;Biological Characteristics;Biological Testing;Bursa-Dependent Lymphocytes;Bursa-Equivalent Lymphocyte;California;Cancers;Cell Surface Receptors;Cells;Clinic;Clinical;Clinical Trials;Companions;Development;Diagnostic;Dose;Dose-Rate;Drug Synthesis And Chemistry;Drugs;Early-Stage Clinical Trials;Fda Approved;Funding;Future;Goals;Hla-Br;Hla-Br Antigens;Hla-D-Related Antigens;Hla-Dr;Hla-Dr Antigens;Hla-Mt;Hla-Mt Antigens;Heterograft;Heterologous Transplantation;Human;Ic50;In Complete Remission;Individual;Inhibitory Concentration 50;Killings;Life;Ligands;Lymphocyte;Lymphocytic;Mabthera;Malignant Neoplasms;Malignant Tumor;Man (Taxonomy);Medication;Mice;Mice Mammals;Modern Man;Molecular Interaction;Murine;Mus;Nih;National Institutes Of Health;Non-Hodgkin's Lymphoma;Nonhodgkins Lymphoma;Normal Cell;P01 Mechanism;P01 Program;Patients;Pharmaceutic Preparations;Pharmaceutical Preparations;Phase;Phase 1 Clinical Trials;Phase I Clinical Trials;Process;Prognosis;Program Project Grant;Program Research Project Grants;Protocol;Protocols Documentation;Public Health;Receptor Protein;Research Program Projects;Risk;Rituxan;Roche Brand Of Rituximab;Sbir;Sbirs (R43/44);Safety;Site;Small Business Innovation Research;Small Business Innovation Research Grant;Surface;Technology;Therapeutic;Therapeutic Agents;Time;Toxic Effect;Toxicities;Toxicology;Translating;Treatment Cost;Treatment Side Effects;Tumor Cell;United States National Institutes Of Health;Universities;Work;Xenograft;Xenograft Model;Xenograft Procedure;Xenotransplantation;Cancer Progression;Clinical Investigation;Clinical Toxicology;Complete Response;Cost;Cost Effective;Cost-Effective;Cytotoxic;Design;Designing;Developmental;Dosage;Drug Synthesis;Drug/Agent;Experience;Improved;Leukemia/Lymphoma;Lymph Cell;Lymphoma/Leukemia;Malignancy;Man;Man's;Meetings;Milligram;Mouse Model;Neoplasm Progression;Neoplasm/Cancer;Neoplastic Cell;Neoplastic Progression;New Therapeutics;Next Generation Therapeutics;Non-Hodgkins Disease;Non-Hodgkins Lymphoma;Novel Therapeutics;Outcome Forecast;Phase 1 Trial;Phase I Protocol;Phase I Trial;Post Treatment;Pre-Clinical;Pre-Clinical Study;Pre-Clinical Trial;Preclinical;Preclinical Study;Preclinical Trial;Public Health Medicine (Field);Receptor;Safety Study;Scale Up;Side Effect;Small Molecule;Success;Therapy Adverse Effect;Treatment Adverse Effect;Tumor;Tumor Growth;Tumor Progression

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.

Thesaurus Terms:
Address;Advanced Malignant Neoplasm;Adverse Effects;Affect;Affinity;Aftercare;Analog;Animals;Apoptosis;B Lymphoid Malignancy;B-Cell Lymphomas;B-Lymphocytes;Binding (Molecular Function);Biological Testing;Biopsy Specimen;California;Canis Familiaris;Cell Growth;Cell Line;Cell Surface Receptors;Cells;Clinic;Clinical;Clinical Trials;Companions;Cost;Cost Effective;Cytotoxic;Cytotoxicity;Data;Design;Diagnosis;Diagnostic;Disease;Dose;Drug Interactions;Drug Kinetics;Drug Structure;Exhibits;Experience;Genotoxicity;Goals;Hepatocyte;Human;Human Tissue;Image;Improved;In Complete Remission;In Vitro;Individual;Killings;Leukemia/Lymphoma;Life;Ligands;Lymphocyte;Malignant Neoplasms;Metabolic;Metabolism;Mitochondria;Monitor;Mouse Model;Mus;Necrosis Induction;Neoplastic Cell;Non-Hodgkin's Lymphoma;Normal Cell;Normal Tissue Morphology;Novel Therapeutics;Outcome Forecast;Overexpression;Pathway Interactions;Patients;Pharmaceutical Preparations;Phase;Phase I Clinical Trials;Phenotype;Preclinical Study;Predisposition;Preparation;Process;Public Health Medicine (Field);Public Health Relevance;Quality Of Life;Radioisotopes;Rattus;Receptor;Reference Standards;Research Clinical Testing;Rituximab;Rodent;Safety;Safety Study;Safety Testing;Site;Small Business Innovation Research Grant;Small Molecule;Success;Surface;Technology;Testing;Therapeutic;Therapeutic Agents;Therapeutic Index;Toxic Effect;Toxicology;Translating;Treatment Cost;Tumor;Tumor Cell Line;Tumor Growth;Universities;Work;Xenograft Model;Xenograft Procedure;