Radioprotectants targeting thrombospondin-1 and CD47
Inventors
Isenberg, Jeffrey S. • Roberts, David D. • Maxhimer, Justin
Assignees
US Department of Health and Human Services
Publication Number
US-8951527-B2
Publication Date
2015-02-10
Expiration Date
2029-08-05
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Described herein is the discovery that cell and tissue survival can be dramatically increased following radiation exposure through inhibition of the interaction between TSP-1 and CD47. This effect is shown using antisense molecules, peptides, and antibodies, which can now be used as radioprotectant agents. These agents find application in minimizing, reducing and/or preventing tissue damage following intentional and accidental radiation exposure, as well as increasing the therapeutic efficacy of radiation therapies by protecting non-target tissue from incidental radiation damage and by increasing tumor ablation following radiation treatment.
Core Innovation
The invention provides methods and agents that dramatically increase cell and tissue survival following radiation exposure by inhibiting the interaction between thrombospondin-1 (TSP1) and CD47 or by suppressing the function of one or both proteins. The discovery shows that antisense molecules, peptides, and antibodies targeting TSP1/CD47 can prevent tissue damage after intentional or accidental radiation exposure and protect non-target tissue during radiation therapy, thereby increasing therapeutic efficacy. Moreover, inhibition of TSP1/CD47 interaction increases tumor ablation in subjects undergoing radiotherapy.
Radiation exposure is known to cause significant cellular and tissue damage through ionization events leading to free radical formation, DNA damage, apoptosis, and inhibition of cell proliferation, particularly affecting tissues with high turnover like bone marrow and mucosal linings. Radiation injury also targets vascular tissues, causing fibrosis, necrosis, and impaired wound healing. There is a vital need for effective radioprotectants to protect normal tissues during diagnostic or therapeutic radiation exposure and to improve therapeutic outcomes by reducing side effects and enhancing tumor ablation efficiency.
Claims Coverage
The patent contains numerous claims primarily directed to methods of protecting tissue from radiation damage and increasing tumor ablation by inhibiting the interaction between TSP1 and CD47. The independent claims cover therapeutic methods asserting use of specific agents and timing of administration.
Method of tissue protection from radiation by inhibiting TSP1-CD47 interaction with specific timing
A method of protecting animal tissue from ionizing radiation damage by administering a therapeutically effective amount of an agent that inhibits the interaction between thrombospondin-1 (TSP1) and CD47, specifically administered within four days prior to and up to one day following radiation exposure.
Use of agents inhibiting TSP1-CD47 interaction to protect subjects exposed to radiation
Methods employing agents that inhibit TSP1 and CD47 interaction to protect tissues of subjects exposed to radioactive substances or ionizing radiation in various contexts including diagnostic, therapeutic, accidental and environmental exposure.
Agents for radioprotection include peptides, antibodies, oligonucleotides, and protein fragments targeting TSP1 or CD47
Use of agents selected from synthetic peptides (e.g., peptides 7N3 and C6d), isolated or recombinant CD47 or TSP1 molecules or their soluble fragments, agents that decrease expression of CD47 or TSP1 including antisense oligonucleotides or morpholinos, CD47 antagonists, and antibodies that specifically bind CD47 or TSP1 to protect tissue from radiation damage.
Methods of increasing tumor ablation in radiotherapy by inhibiting TSP1-CD47 interaction
Methods that increase tumor cell killing during radiotherapy in subjects by prior administration of agents that inhibit interaction between TSP1 and CD47, using similar classes of agents as described for radioprotection.
The claims collectively cover methods of tissue radioprotection and enhanced tumor ablation by application of agents inhibiting TSP1-CD47 interaction, including a broad group of peptides, antibodies, antisense oligonucleotides, and protein fragments, administered around the time of radiation exposure.
Stated Advantages
Dramatic increase in cell and tissue survival following radiation exposure through inhibition of TSP1-CD47 interaction.
Minimization, reduction, and prevention of tissue damage from both intentional and accidental radiation exposure.
Selective protection of non-target normal tissues during radiotherapy, thereby increasing therapeutic efficacy without compromising tumor ablation.
Increased tumor ablation in subjects undergoing radiotherapy by protecting immune cells and enhancing anti-tumor immune response.
Applicability to a wide range of radiation types, doses, and exposure scenarios including diagnostic and therapeutic uses as well as accidental or environmental radiation exposure.
Documented Applications
Minimizing, reducing, and preventing tissue damage following intentional and accidental radiation exposure.
Increasing therapeutic efficacy of radiation therapies by protecting non-target tissue from incidental radiation damage.
Increasing tumor ablation in subjects undergoing radiotherapy.
Protection of personnel exposed to radioactive substances or ionizing radiation such as nuclear warfare, nuclear accidents, space flight, and radiological diagnostics.
Use as pharmaceutical agents to prevent or treat radiation-induced injury in normal tissues and enhance cancer radiotherapy outcomes.
Interested in licensing this patent?