Anti radiation Antidote: Inhibition and neutralization of Radiation Toxicity with Therapeutic Monoclonal Antibodies .

DMITRI POPOV. PHD, RADIOBIOLOGY. MD (RUSSIA)

ADVANCED MEDICAL TECHNOLOGY AND SYSTEMS INC. CANADA. INTERVACCINE@GMAIL.COM

DOI: 10.13140/RG.2.1.1476.6805

Anti radiation Antidote: Inhibition and neutralization of Radiation Toxicity with Therapeutic Monoclonal Antibodies .

Anti radiation Therapeutic Monoclonal Antibodies.

Antibodies become a clinically important drug class: more than 25 antibodies are approved for human therapy and more than 300 antibodies are currently in clinical development worldwide for a wide range of diseases, including autoimmunity and inflammation, protection against radiation cancer , organ transplantation, cerebrovascular disease, cardiovascular disease, infectious diseases and ophthalmological diseases. http://www.nature.com/nri/journal/v10/n5/abs/nri2761.htmlhttps://www.google.ca/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-8#q=radiation%20toxinshttp://pubmedcentralcanada.ca/pmcc/articles/PMC3929455/

Anti radiation Therapeutic Monoclonal Antibodies.

Cytokine and growth factor blockade. The first therapeutic antibody for the treatment of inflammatory diseases was infliximab (Remicade; Centocor/Merck), in 1998, for the treatment of Crohn’s disease. Mechanisms of action of therapeutic antibodies. Five non-overlapping mechanisms of action are depicted. Examples of therapeutic antibodies are listed for each mechanism of action depicted. Ligand blockade with full length IgG therapeutic antibodies (for example, infliximab, adalimumab or golimumab), antibody fragments (for example, certolizumab pegol) or receptor immunoadhesins (for example, etanercept and those indicated with ‡) can prevent ligands from activating their cognate receptors. http://www.nature.com/nri/journal/v10/n5/abs/nri2761.html

Anti inflammatory therapeutic antibodies. Mechanisms of action.

Binding of ligands (for example, interleukin-6 (IL-6)) to receptors (for example, IL-6R) can also be blocked by antibodies directed to their cognate receptors and inhibit receptor activation or function. Binding of cell surface receptors by antibodies can also result in

their internalization and downregulation to limit cell surface receptors that can be activated by the ligand. Binding of cell surface receptors by antibodies (for example, αL integrin by

efalizumab) or binding of a ligand (for example, free serum IgE by omalizumab) can indirectly also result in downregulation of cell surface

receptors available for cellular activation. Binding of cell surface receptors can result in depletion of antigen-bearing cells through complement-mediated lysis and opsonization, as well

as Fc receptor for IgG (FcγR)-mediated clearance. http://www.nature.com/nri/journal/v10/n5/abs/nri2761.html

Anti inflammatory therapeutic antibodies. Mechanisms of action.

Therapeutic antibodies can also induce active signals that alter cellular fates. Binding of the T cell receptor (TCR)–CD3

complex by teplizumab can induce TCR-mediated signals and alter T cell functions and differentiation. MAC, membrane attack complex; TNF, tumour necrosis factor; TNFRI; TNF receptor I. *Antibodies with several mechanisms of action.

Receptor blockade and receptor modulation. in addition to ligand blockade, therapeutic antibodies can also block ligand–receptor interactions by targeting the

receptor . These include antibodies that target the il-6 receptor (tocilizumab (Actemra/RoActemra; Chugai/Roche)), αl integrin (also known as CD11a

and lFA1) (efalizumab (Raptiva/Xanelim; Genentech/Roche/Merck–Serono)), the α4 subunit of α4β1 and α4β7 integrins (natalizumab (Tysabri; Biogen idec/Elan)) and α4β7 integrin (vedolizumab (MlN2; Millennium Pharmaceuticals/Takeda)). Targeting of receptors adds a

secondary level of mechanistic activity as a subset of these therapeutic antibodies not only blocks ligand binding butalso downregulates the cell surface expression of the targeted receptors.

http://www.nature.com/nri/journal/v10/n5/abs/nri2761.html

Anti Radiation Therapeutic Monoclonal Antibodies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005344/ Acute Radiation Disease include Five Syndromes: Acute Radiation Cerebrovascular Syndrome. Acute Radiation Cardiovascular Syndrome. Acute Radiation Gastro Intestinal Syndrome. Acute Radiation Hematopoietic Syndrome. Acute Radiation Immunologic Syndrome, which include Acute

Radiation Systemic Inflammatory Response Syndrome, and Acute Radiation Systemic Autoimmune Syndrome .

http://www.slideshare.net/dlpopov/acute-radiation-diseasedefinition

Anti radiation Therapeutic Monoclonal Antibodies.

Systemic inflammatory response syndrome (SIRS) is an inflammatory state affecting the whole body, frequently a response of the immune system to radiation or  infection.

It is related to sepsis or high doses of Radiation, a condition in which individuals meet criteria for SIRS and have a known infection or irradiated with high doses of Radiation such as gamma radiation, heavy ion radiation, neutron radiation, proton radiation, X ray radiation. SIRS is a sysytemic condition related to systemic inflammation, organ dysfunction, and organ failure. It is a subset of cytokine storm, in which there is abnormal regulation of various cytokines. SIRS is also closely related to sepsis, in which patients satisfy criteria for SIRS and have a suspected or proven infection.

Monoclonal Antibodies.

SIRS is also closely related to high doses of radiation and cell necrosis induced by irradiation , in which patients satisfy criteria for SIRS and have a suspected or proven post radiation status.

https://www.google.ca/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-8#q=radiation%20toxins

Monoclonal Antibodies.

Radiation Toxic Multiple organ dysfunction syndrome (RT MODS), previously known as Radiation Toxic multiple organ failure (RT MOF) or Radiation Toxic multisystem organ failure (RT MSOF), is altered organ function in an irradiated patients.

https://www.google.ca/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-8#q=radiation%20toxins

Monoclonal Antibodies and Acute Radiation Cytokine Storm.

A cytokine storm, also known as cytokine cascade and hypercytokinemia, is a potentially fatal immune reaction consisting of a positive feedback loop between cytokines and white blood cells, with highly elevated levels of various cytokines.

Local and systemic responses are initiated by tissue damage after irradiation by Reactive Oxygen Species, Reactive Nitrogen Species, Hydrolytic Enzymes and secondary by cytokine activation. Respiratory failure is common in the first 72 hours after the original insult. Subsequently, one might see liver failure ( 1–7 days), gastrointestinal bleeding (hours–days) and kidney failure (11–17 days)

Monoclonal Antibodies.

Acute Radiation Vasculitis. http://

www.slideshare.net/dlpopov/acuteradiation-disease-acute-radiation-vasculitis

Acute Radiation Angioedema. https://

www.google.ca/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-8#q=radiation+angioedema

http://www.ncbi.nlm.nih.gov/books/NBK209/ https://books.google.ca/books?id=40Z9CAAAQBAJ&pg=RA6-

PA35&lpg=RA6-PA35&dq=radiation+angioedema&source=bl&ots=SlzS6mbrMR&sig=Ywhd964EFhJy3Rg5CJtZ1uRr2Qc&hl=en&sa=X&ved=0CEEQ6AEwBmoVChMIiJaQ_c69yAIVCaUeCh2ZZAkp#v=onepage&q=radiation%20angioedema&f=false

Therapeutic Monoclonal Antibodies and Radiation Angioedema.

Angioedema with swelling of larynx is a serious allergic reaction and can be life-threatening. It can occur after exposure to various triggers and usually it is very difficult for the patient and the doctor to find the trigger and maintain complete remission. In idiopathic recurring angioedema presenting with frequent attacks, prophylaxis with H1 antihistamines recommended. However, not all patients respond to antihistamines. Omalizumab is an anti-immunoglobulin (Ig)-E-Ig-G antibody approved for the treatment of asthma and also effective treatment in chronic spontaneous urticaria. We report a 47-year-old male patient with severe idiopathic angioedema controlled by corticosteroid and proggressed after discontining of corticosteroid because of its side effects. Omalizumab at a dose of 300 mg every 4 weeks was administrated and omalizumab provided a rapid clinical response after first injection. During the 4 months of omalizumab therapy, he had no further attacks and any other treatment needs. After 3 months of stopping omalizumab therapy, during the 4-week period he had two mild lip swelling in his lips that resolved with antihistamines. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4005344 /

Asia Pac Allergy. 2014 Apr; 4(2): 129–130. Ayse Bilge Ozturk et al. Published online 2014 Apr 29. doi:  10.5415/apallergy.2014.4.2.129

Monoclonal Antibodies.

Acute Radiation Hepatitis. http://www.ajronline.org/doi/abs/10.2214/ajr.117.1.73 http://www.ncbi.nlm.nih.gov/pubmed/547358 http://onlinelibrary.wiley.com/doi/10.1002/hep.510260117/pdf

Monoclonal Antibodies.

Acute Radiation Pneumonitis. Radiation pneumonitis is the acute manifestation

of radiation-induced lung disease (RILD) and is relatively common following radiotherapy for chest wall or intrathoracic malignancies. This article does not deal with changes seen in the the late phase.

Radiation pneumonitis - Radiopaedia.org radiopaedia.org/articles/radiation-pneumonitis http://www.cancer.ca/en/cancer-information/diagnosis-and-treatm

ent/radiation-therapy/side-effects-of-radiation-therapy/radiation-to-the-chest/radiation-pneumonitis/?region=on

http://jjco.oxfordjournals.org/content/29/4/192.full

Monoclonal Antibodies and bone marrow protection and resistance against radiation.

Acute Radiation Hematopoietic Syndrome.

Monoclonal Antibodies.

Acute Radiation Immunologic Syndrome: Sub Type - Acute Radiation Autoimmune processes.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935336/ http://www.ncbi.nlm.nih.gov/pubmed/8133066 http://press.endocrine.org/doi/full/10.1210/jc.2005-0286 https://

flutrackers.com/forum/forum/welcome-to-the-scientific-library/radiation-exposure-effects-on-humans-food-chain-environment/117546-radiation-and-autoimmune-disease

Monoclonal Antibodies.

Scientists at the Stanford University School of Medicine found that "Ionizing radiation can functionally alter the immune system and break self-tolerance"(a technical term for when radiation breaks down the normal ability to fight off disease). The study is published in the Journal of Immunology. The researchers irradiated the thymus and the peripheral lymphoid organs/tissues in mice to induce the autoimmune response. Total lymphoid irradiation on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. They concluded, "these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system."

Monoclonal Antibodies.

http://www.ncf-net.org/radiation/LoganovskyLowDoseIonizingRadiationBrain.pdf

Radiation exposure has multiple effects on the brain, behavior, and cognitive functions. These changes depend largely on the dose received. It is well known that ionizing radiation influences CNS functions and behavior both as a result of direct effects on the nervous system and indirectly through CNS reactivity to the radiation damage of other systems (Kimeldorf & Hunt, 1965; Mickley, 1987)

Monoclonal Antibodies.

According to the data of the State Register of Ukraine and Clinical and Epidemiological Registry (Scientific Centre for Radiation Medicine, Kiev) there is an increased level of cerebrovascular disorders in liquidators and evacuees. Exposure to small doses of ionizing radiation is a significant risk factor of accelerating aging. Thyroid exposure by 300 mGy and more is a significant risk factor for vascular and cerebrovascular disorders. Thyroid exposure by 2 Gy and more is a significant risk factor for mental disorders, vascular and cerebrovascular diseases, and peripheral nervous system disorders. Exposure to doses of 250 mGy and more is a significant risk factor for neuropsychiatric disorders and vascular disorders. There is a dose–effect relationship for cerebrovascular disorders in liquidators – military and civic personnel. http://www.ncf-net.org/radiation/LoganovskyLowDoseIonizingRadiationBrain.pdf

Monoclonal Antibodies.

Occupational exposure and neurotoxicity of Uranium and transuranium elements: implementation at the Shelter Object of the Chernobyl NPP .

Monoclonal Antibodies.

The available data on neuropsychiatric effects of occupational exposure are quite limited and contradictory. The most comprehensive related study was conducted by Azizova (1999) in atomic industry workers exposed to chronic occupational ionizing radiation, mainly external γ-irradiation. Vegetative-vascular dystonia, predominantly hypothensive, asthenic syndrome, and demyelinizating encephalomyelosis syndrome were the main neurological clinical patterns. Their rate was in proportion to the radiation dose. Together with hematological abnormalities (thrombocytopenia and leukocytopenia), these were considered to be the neurological features of Chronic Radiation Sickness. Demyelinizating encephalomyelosis was observed only at doses of 2–4 Sv and more. Cerebrovascular pathology was the most common in the remote period after irradiation. Radiation risk for cerebral atherosclerosis has been revealed; however, no connection between the dose and stroke rate has been found.

http://www.ncf-net.org/radiation/LoganovskyLowDoseIonizingRadiationBrain.pdf

Specific Therapeutic Monoclonal Antibodies – Anti radiation Antidote. .

Impression: Acute Radiation Disease include development of radiation

toxicity after Reactive Oxygen Species, Reactive Nitrogen Species, Hydrolytic enzyme leakage from lysosomes and Golgi apparatus , radiation cell necrosis, regional and general inflammation, vasculitis, acute autoimmune reactions development.

Specific Therapeutic Monoclonal Antibodies can play role of Anti Radiation Antidote and inhibit hydrolytic enzyme activation and toxicity, prevent inflammation and autoimmune reactions.

Specific Therapeutic Monoclonal Antibodies can protect mammals against high doses of radiation and biological sequela after radiation.