Engineering'of'Human'H.NOX'as'an'Oxygen'Delivery'Therapeutic'for'Prolonged'Administration'' ' Project Summary/Abstract Omniox has developed a class of tunable oxygen-delivery agents that significantly alleviate tumor hypoxia to enhance the efficacy of radiotherapy (RT). This family of therapeutic proteins, called H-NOX, can oxygenate hypoxic tumors without the treatment burden and toxicity associated with earlier oxygenation therapies. Because radiation relies on oxygen to damage DNA, the lack of oxygen in aggressive solid tumors is a major impediment to effective treatment. Previous SBIR-funded studies resulted in the identification of an H-NOX variant of bacterial origin, OMX-4.80, that is highly effective in penetrating and oxygenating hypoxic tumors and enhancing tumor growth delay after single radiation treatments. OMX-4.80 does not result in cardiovascular, renal, or hypertensive toxicities associated with hemoglobin-based oxygen carriers. The bacterial origin of the lead candidate makes it appropriate for hypofractionated RT-such as Cyberknife" for metastatic brain and recurrent primary brain cancer-however, its immunogenicity is incompatible with prolonged dosing schemes (>2 weeks) of fractionated RT in >80% of the 800,000 patients that receive RT. In this study, we will evaluate a novel class of therapeutic oxygen carriers from human H-NOX (hH-NOX) homologues, which have been engineered with similar oxygen delivery properties to OMX-4.80, yet remain compatible with the prolonged treatment schedules currently used in fractionated RT. We have screened a focused mutant library of 180 hH-NOX variants, and identified 10 candidates with promising oxygen-binding kinetics.
In Aim 1, Omniox will compare the oxygen affinity, stability and NO reactivity of this panel of 10 candidates to identify a lead candidate (and backups) with optimal biochemical properties.
In Aim 2, animal studies will be performed to characterize the pharmacokinetic, safety and immunogenicity profile of the lead candidate.
In Aim 3, using a syngeneic tumor xenograft model in immunocompetent mice developed and tested during Omniox'preclinical development of the bacterial H-NOX, we will examine tumor biodistribution and oxygenation of the lead hH-NOX (Aim 3A) and demonstrate reduction in primary tumor growth through repeated hH-NOX dosing in conjunction with fractionated RT (Aim 3B).! ! ' CONFIDENTIAL (c)2013 Omniox, Inc. NOT FOR DISTRIBUTION

Public Health Relevance

This project will develop a novel oxygen delivery therapeutic derived from the human H-NOX (hH-NOX) protein that is suitable for repeated dosing in fractionated radiotherapy schedules. This therapeutic will effectively oxygenate hypoxic niches in tumors and improve radiotherapy to reduce tumor growth in cancer patients without the dramatic toxicities associated with hemoglobin-based oxygen carriers (HBOCs) or potential immunogenic reactivity of bacterial H-NOX homologues. If successful, this study will identify a highly innovative hH-NOX therapeutic candidate that meets the necessary product profile for sensitization of fractionated radiotherapy in a broad range of cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43CA177097-01A1
Application #
8648430
Study Section
Special Emphasis Panel (ZRG1-OTC-R (11))
Program Officer
Kurtz, Andrew J
Project Start
2014-09-19
Project End
2015-08-31
Budget Start
2014-09-19
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$225,000
Indirect Cost
Name
Omniox, Inc.
Department
Type
DUNS #
786563036
City
San Carlos
State
CA
Country
United States
Zip Code
94070