Radiation Antidote for Defense

Despite the significant threat of high dose radiation exposure that exists in our world today, there are currently no highly effective and non-toxic anti-radiation treatments available. CBLI is building upon its understanding of the molecular mechanisms by which radiation induces cell death to develop pharmaceuticals that address this need. CBLI’s Protectan compounds rescue mammals from lethal doses of radiation by suppressing apoptotic cell death in critical hematopoietic (HP) and/or gastrointestinal (GI) tract cells. The effectiveness of Protectans whether injected before or after radiation exposure indicates that these compounds have great potential as practical, as well as effective and non-toxic, biodefense measures.
Background and Rationale
With rogue nations developing nuclear capabilities and almost 30,000 nuclear warheads deployed around the world, the possibility of nuclear warfare is an unfortunate reality. In addition, the risk of a terrorist attack involving either a nuclear weapon, a “dirty bomb” (a combination of conventional explosives and nuclear material), or an attack on a nuclear power plant or waste site is a top concern for many countries. The possibility of an accident at a nuclear power plant (104 in the U.S. and 439 worldwide) presents another potentially daunting source of radiation. A Nuclear Regulatory Commission study stated that breaching a cask of spent fuel could release lethal radiation over an area many times larger than that affected by a 10 kiloton nuclear weapon.

The need for countermeasures against these threats is dire since there are currently no pharmaceuticals approved for use in protecting humans from acute radiation injury. The only agent that has been widely stockpiled to date for use in the event of an act of nuclear terrorism or a nuclear accident is potassium iodide (KI). However, KI is only effective against the long-term risk of cancer developing ten to fifteen years post-exposure. It does not protect the body from the acute effects of high dose radiation that can lead to death within days or weeks.

The short term lethality of high dose ionizing radiation is due to development of Acute Radiation Syndrome (ARS) caused by massive apoptosis in radiosensitive organs, including the hematopoietic (HP) system and the gastrointestinal (GI) tract. Other cell types, such as spermatocytes and hair follicles, are also affected. HP and GI acute radiation syndromes are induced by different levels of radiation and have highly predictable clinical courses. In humans, whole-body or significant partial body exposure to less than 3.5 Gy results in only moderate bone marrow (HP) damage and survival is probable. However, survivors are likely to suffer from severe immunosuppression and/or an increased risk of cancer. Exposure to 3.5-7.5 Gy induces severe bone marrow damage and death is probable within 2-6 weeks. Significant GI damage occurs in addition to HP damage at doses over 5 Gy, and at doses over 7.5 Gy, death typically occurs within 1-2 weeks. At doses of 10 Gy and higher, cerebrovascular dysfunction becomes a leading factor in death within days. It is estimated that nearly all survivors of the 1945 blast at Hiroshima received doses of less than 3 Gy. Chernobyl firefighters were likely exposed to 6-7 Gy.

CBLI’s unique approach of pharmacological modulation of apoptosis is ideally suited to address the need for effective radiation countermeasures. The company is currently developing derivatives of microbial factors that are natural regulators of apoptosis as Protectans, molecules that prevent death of normal cells in the face of stresses such as radiation. As described below, the lead Protectan compounds CBLB502 and CBLB600 series have significant activity as both radioprotectants (injected prior to radiation exposure) and mitigators of radiation damage (injected after radiation exposure). The underlying principle of radioprotection by Protectans and their structures and uses represent the intellectual property of CBLI developed in collaboration with the Cleveland Clinic.

Lead Compounds
Protectan CBLB502

Protectan CBLB502 is a rationally designed recombinant derivative of the bacterial protein, flagellin, which binds and activates the mammalian TLR5 cell surface receptor. CBLI initially chose to explore flagellin as a potential radioprotectant since its signaling through TLR5 is known to activate the anti-apoptotic NF-kappaB pathway. Moreover, TLR5 is expressed on the endothelial cells of the small intestine lamina propria, the most radiosensitive part of the GI tract.

Extensive preclinical studies have demonstrated that CBLB502 is an effective and non-toxic anti-radiation treatment. The compound rescues both mice and non-human primates (Macaca mulatta) from lethal doses of total body gamma radiation, whether injected prior to, or after, radiation exposure. CBLB502 is non-toxic at therapeutic doses in both mice and monkeys. Importantly, CBLB502 protects cells of both the HP system and the GI tract. GI protection is a unique advantage of CBLB502 over any currently known radioprotectant or radiomitigator. CBLB502 is highly stable and is effective when administered through intramuscular injection, characteristics important for practical application as an emergency or military field treatment.

CBLB502 Development Status: CBLI initiated preclinical studies of CBLB502 as a radioprotectant for medical applications, such as Supportive Care in Cancer Treatment, and is progressing towards clinical development of the drug for such uses, expected in 2008. However, since CBLB502 also presents a highly promising approach to biodefensive radioprotection, CBLI is currently focused on expedited development of the drug for “non-medical” biodefense applications. New U.S. Food and Drug Administration (FDA) regulations eliminate the requirement for Phase II and Phase III clinical trials for investigational drugs that address situations such as radiation injury since it would be infeasible and/or unethical to conduct efficacy studies in humans. In such cases, drugs are considered for approval based upon only Phase I safety studies in humans and efficacy studies in two animal species (the FDA “Animal Efficacy Rule”). Accelerated preclinical development of CBLB502 under this rule is being supported in part by a contract from the Defense Threat Reduction Agency (DTRA) of the Department of Defense (DoD) received in March 2007. In addition, CBLI submitted CBLB502 to the DoD in response to a Request for Proposal (RFP) #W9113M-07-R-0002 for medical radiation countermeasures to treat the GI effects of acute radiation syndrome. The RFP award would fund the remaining steps of development through FDA approval and include a commitment to purchase up to 500,000 doses of the drug. Unlike any known competitor, CBLB502 fulfills two key requirements of the RFP: effectiveness when administered post-exposure and protection of GI acute radiation syndrome. It is expected that this contract will be awarded in 4Q07. CBLI expects to submit an NDA for FDA approval in less than two years. Preclinical studies, cGMP manufacturing and a pre-IND meeting have been completed. CBLI is poised to submit its IND application and initiate the human safety trial. Investigation of the drug’s extended stability, final formulation and delivery devices is ongoing.

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CBLB600 Series Protectans
In addition to CBLB502, CBLI is also investigating the radioprotective potential of a series (CBLB600 Series Protectans) of pharmacologically improved synthetic derivatives of mycoplasma lipopeptide. Mycoplasma lipopeptide is the natural agonist of heterodimeric TLR2/TLR6 receptors expressed on mammalian cells. Signaling through this receptor results in activation of the anti-apoptotic NF-kappaB pathway.

Preclinical investigation of CBLB600 Series compounds as radioprotectants has demonstrated that they protect mice from death due to HP acute radiation syndrome when administered either before or after radiation exposure. The compounds are non-toxic at therapeutic doses in mice, are highly stable, and can be effectively delivered by intramuscular or subcutaneous injection. Studies are currently under way to examine the radioprotective/mitigative efficacy of CBLB600 Series Protectans in non-human primates.

A striking feature of CBLB600 Series Protectans is that, in the absence of irradiation, their administration stimulates proliferation of bone marrow hematopoietic stem cells and induces their migration to the peripheral blood. Stem cell induction may contribute to the radioprotective/mitigative effects of CBLB600 Series Protectans, and also has a wide range of other potential applications.

While Protectan CBLB502 is uniquely efficient in protecting the GI tract, CBLB600 Series Protectans have other advantages that highlight their strong potential as radiation antidotes complementing the use of CBLB502 for defense applications. Being non-immunogenic and highly immunostimulatory, CBLB600 Series compounds have a wide time window of effective administration. A single injection provides protection for 72 hours. Moreover, the compounds are effective when injected up to 24 hours post-irradiation. Another important advantage of CBLB600 Series Protectans lies in their unique protection of the functional immune system. In addition to early HP progenitor cells, CBLB600 Series compounds also protect mature immunocytes, thus reducing the severity of temporary immunosuppression following irradiation. Maintenance of the immune system is also important for reducing side effects associated with chemotherapy, another projected area of application for CBLB600 Series Protectans.

Like Protectan CBLB502, CBLB600 Series compounds are eligible for expedited development for biodefense applications under the FDA “Animal Efficacy Rule.” Extensive pre-clinical experiments have been completed in mice. These include efficacy, toxicity and pharmacokinetics studies. The efficacy stage of non-human primate experiments is ongoing.

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