Chemistry:Entolimod

Short description: Chemical compound

Entolimod

Clinical data
Other names	CBLB502
Legal status
Legal status	Investigational
Identifiers
CAS Number	951628-22-1
ChemSpider	none
UNII	R1UQ6D1ECM
KEGG	D10368
Chemical and physical data
Formula	C1464H2419N457O519S8
Molar mass	34983.62 g·mol−1

Entolimod (CBLB502) is being developed by Cleveland Biolabs, Inc. for dual indications under the U.S. Food & Drug Administration’s (FDA) animal efficacy rule as a pivotal-stage radiation countermeasure, and under the FDA’s traditional drug approval pathway as a cancer treatment.

Entolimod is a recombinant protein that acts as an agonist of toll-like receptor 5 (TLR5), an innate immunity receptor. Entolimod activation of TLR5 triggers NF-κB signaling, mobilizing an innate immune response that drives the expression of numerous genes, including inhibitors of apoptosis, scavengers of reactive oxygen species, and a spectrum of protective or regenerative cytokines.

Radiation countermeasure

The FDA established the animal efficacy rule in 2002 to permit the approval of certain drugs and biologics that are intended to reduce or prevent serious or life-threatening conditions based on evidence of safety from trial in healthy subjects and effectiveness from appropriate animal studies when human efficacy studies are not ethical or feasible.

Efficacy of entolimod as a radiation countermeasure has been assessed in animal models. These studies demonstrate that a single administration of entolimod given either before or after lethal total body irradiation leads to significant improvement in animal survival. Entolimod has been shown to reduce radiation damage to both hematopoietic (HP) and gastrointestinal (GI) tissues and improve tissue regeneration.

Two clinical studies that involved administration of a range of doses of entolimod in 150 healthy human subjects have been completed. Both studies demonstrated that administration of entolimod appears to be safe within a certain dose range. The most frequent adverse event associated with entolimod administration was a transient flu-like syndrome, which is consistent with the mechanism of action of the compound.

The FDA granted entolimod both Fast Track and Orphan Drug status for reducing the risk of death following a potentially lethal dose of total body irradiation during or after a radiation disaster.

Both the Department of Health and Human Services and the Department of Defense procure and maintain medical stockpiles to respond to bioterrorist and emerging infectious disease outbreaks. Under a declared state of emergency, countermeasures may be procured for the Strategic National Stockpile under an Emergency Use Authorization prior to their full FDA licensure approval.

Oncology

Preclinical studies have shown that entolimod has a suppressive effect on growth of TLR5 expressing tumors. Entolimod has also been shown to have an effect on several animal models of liver metastasis, regardless of TLR5 expression. Additionally, entolimod evidences a supportive care benefit in preclinical models when combined with radiation treatment and cytotoxic agents with adverse gastrointestinal (GI) effects. Tissue protective effects of TLR5 agonists are limited to normal tissues and do not involve protection of tumors from treatment.

A Phase I advanced solid tumor study is currently ongoing at Roswell Park Comprehensive Cancer Center. The Principal Investigator for this trial is Alex Adjei, M.D., Ph.D., FACP, Chair of the Department of Medicine and Senior Vice President of Clinical Research at Roswell Park Comprehensive Cancer Center.

Additionally, entolimod may also be developed as an adjuvant to standard radiation and chemotherapy, which will allow using of more aggressive measures to attack malignant cells and increase the effectiveness of cancer treatment.

Further reading

• "Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist". Proceedings of the National Academy of Sciences of the United States of America 110 (20): E1857-66. May 2013. doi:10.1073/pnas.1222805110. PMID 23630282. Bibcode: 2013PNAS..110E1857B. 
• "A TLR5 agonist enhances CD8(+) T cell-mediated graft-versus-tumor effect without exacerbating graft-versus-host disease". Journal of Immunology 189 (10): 4719–27. November 2012. doi:10.4049/jimmunol.1201206. PMID 23045613. 
• "Identification of granulocyte colony-stimulating factor and interleukin-6 as candidate biomarkers of CBLB502 efficacy as a medical radiation countermeasure". The Journal of Pharmacology and Experimental Therapeutics 343 (2): 497–508. November 2012. doi:10.1124/jpet.112.196071. PMID 22837010. 
• "Structural basis of TLR5-flagellin recognition and signaling". Science 335 (6070): 859–64. February 2012. doi:10.1126/science.1215584. PMID 22344444. Bibcode: 2012Sci...335..859Y. 
• Mueller, K. L. (2012). "Flagellin Takes Its Toll". Science Signaling 5 (212): ec62. doi:10.1126/scisignal.2002965. Bibcode: 2012Sci...335T.774.. 
• "Toll-like receptor 5 agonist protects mice from dermatitis and oral mucositis caused by local radiation: implications for head-and-neck cancer radiotherapy". International Journal of Radiation Oncology, Biology, Physics 83 (1): 228–34. May 2012. doi:10.1016/j.ijrobp.2011.05.055. PMID 22000579. 
• "A TLR5 agonist inhibits acute renal ischemic failure". Journal of Immunology 187 (7): 3831–9. October 2011. doi:10.4049/jimmunol.1003238. PMID 21890657. 
• "An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models". Science 320 (5873): 226–30. April 2008. doi:10.1126/science.1154986. PMID 18403709. Bibcode: 2008Sci...320..226B. 
• "The structure of the TLR5-flagellin complex: a new mode of pathogen detection, conserved receptor dimerization for signaling". Science Signaling 5 (216): pe11. March 2012. doi:10.1126/scisignal.2002963. PMID 22434932. 
• "Activation of Toll-like receptor 5 on breast cancer cells by flagellin suppresses cell proliferation and tumor growth". Cancer Research 71 (7): 2466–75. April 2011. doi:10.1158/0008-5472.CAN-10-1993. PMID 21427357. 
• "Medicine. Drug bestows radiation resistance on mice and monkeys". Science 320 (5873): 163. April 2008. doi:10.1126/science.320.5873.163. PMID 18403680.