Development of a Therapeutic TNF Degradation Product

Award Information
Agency: Department of Health and Human Services
Branch: N/A
Contract: N/A
Agency Tracking Number: 22005
Amount: $50,000.00
Phase: Phase I
Program: SBIR
Awards Year: 1993
Solicitation Year: N/A
Solicitation Topic Code: N/A
Solicitation Number: N/A
Small Business Information
Oncotech, Inc.
1791 Kaiser Avenue, Irvine, CA, 92714
DUNS: N/A
HUBZone Owned: N
Woman Owned: N
Socially and Economically Disadvantaged: N
Principal Investigator
 John P. Fruehauf
 (714) 474-9262
Business Contact
Phone: () -
Research Institution
N/A
Abstract
Recombinant human tumor necrosis factor-alpha (TNF) has had only modest success in clinical trials, in part because of dose limiting toxicities. To fully realize TNF's clinical activity, it will be necessary to develop more potent TNF analogues possessing fewer untoward effects. Several studies have found that TNF cytotoxicity depends on TNF internalization and processing by the cell. We compared the processing of TNF by TNF-sensitive and resistant cancer cells of breast and prostate origins. Sensitive cells were found to process internalized TNF to 15 kD and 5.5 kD species, while the resistant cell lines produced multiple lower molecular weight TNF products. We also evaluated the toxicity of conditioned medium from sensitive cells to determine if media containing the degradation products was toxic to resistant cells. Hydrophobic interaction column HPLC was employed to isolate and purify the degradation products for evaluation of their cytotoxic activity. Conditioned media and the HPLC fractions of conditioned media enriched for the 5.5 kD TNF fragment were toxic to both TNF-sensitive and -resistant tumor cells. Phase I would isolate, sequence and synthesize the 5.5 kD degradation product and assay its antineoplastic activity against fresh human tumors of various histology's. If Phase I results are encouraging, Phase II would evaluate the toxicity profile and anti-tumor action of this peptide in vivo in murine models. The ultimate goal would be to develop a new chemotherapeutic agent.

* information listed above is at the time of submission.

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