Guillian-Barre.Therapy.Experimental.

Guillain-Barre : Protease Inhibition.

Dmitri Popov. PhD, Radiobiology.

MD (Russia)

Advanced Medical Technology and Systems Inc. Canada.

[email protected]

Guillian-Barre.

• Research Proposal: Guillian-Barre : Protease Inhibition.

• Dmitri Popov

• Full-text · Research Proposal · Jan 2015

• File name: Guillian-Barre.Therapy.Experimental..pptxDOI: 10.13140/RG.2.1.4913.5122

•

Guillain-Barre : Protease Inhibitors.

• Proteases are ubiquitous in all living cells. As soon as cells are disrupted, proteases are released and can quickly degrade any protein. This can drastically reduce the yield of protein during isolation and purification.

• Contaminating proteases can be inhibited by protease inhibitors, thereby protecting the protein of interest from degradation.

• http://iti.stanford.edu/content/dam/sm/iti/documents/himc/immunoassays/ProteaseInhibitionGuide.pdf

Guillain-Barre: Protease Inhibitors.

• A protease (also called a peptidase or proteinase) is any enzyme that performs proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in a polypeptide chain.

• Proteases have evolved multiple times, and different classes of protease can perform the same reaction by completely different catalytic mechanisms. Proteases can be found in animals, plants, bacteria, archaea and viruses.

• https://en.wikipedia.org/wiki/Protease

Guillain-Barre: Protease Inhibitors.

• Proteases can be classified into seven scientific groups:

• Serine proteases - using a serine alcohol

• Cysteine proteases - using a cysteine thiol

• Aspartate proteases - using an aspartate carboxylic acid

• Threonine proteases - using a threonine secondary alcohol

• Glutamic acid proteases - using a glutamate carboxylic acid

• Metalloproteases - using a metal, usually zinc

• Asparagine peptide lyases - involve asparagine, but they are a type of proteolytic enzymes different from those above.

• https://en.wikipedia.org/wiki/Protease

Guillain-Barre : Protease Inhibitors.

• The mechanism used to cleave a peptide bond involves making an amino acid residue that has the cysteine and threonine (proteases) or a water molecule (aspartic acid, metallo- and glutamic acid proteases) nucleophilic so that it can attack the peptide carboxyl group. One way to make a nucleophile is by a catalytic triad, where a histidine residue is used to activate serine, cysteine, or threonine as a nucleophile. This is not an evolutionary grouping, however, as the nucleophile types have evolved convergently in different superfamilies, and some superfamilies show divergent evolution to multiple different nucleophiles.

• https://en.wikipedia.org/wiki/Protease

Guillain-Barre: Protease Inhibitors.

• Proteases occur in all organisms, from prokaryotes to eukaryotes to viruses. These enzymes are involved in a multitude of physiological reactions from simple digestion of food proteins to highly regulated cascades (e.g., the blood-clotting cascade, the complement system, apoptosis pathways, and the invertebrate prophenoloxidase-activating cascade). Proteases can either break specific peptide bonds (limited proteolysis), depending on the amino acid sequence of a protein, or break down a complete peptide to amino acids (unlimited proteolysis). The activity can be a destructive change (abolishing a protein's function or digesting it to its principal components), it can be an activation of a function, or it can be a signal in a signalling pathway.

• https://en.wikipedia.org/wiki/Protease

Guillain-Barre: Protease Inhibitors.

• Proteases are used throughout an organism for various metabolic processes. Proteases present in blood serum (thrombin, plasmin, Hageman factor, etc.) play important role in blood-clotting, as well as lysis of the clots, and the correct action of the immune system. Other proteases are present in leukocytes (elastase, cathepsin G) and play several different roles in metabolic control. Some snake venoms are also proteases, such as pit viper haemotoxin and interfere with the victim's blood clotting cascade. Proteases determine the lifetime of other proteins playing important physiological role like hormones, antibodies, or other enzymes. This is one of the fastest "switching on" and "switching off" regulatory mechanisms in the physiology of an organism.

• By complex cooperative action the proteases may proceed as cascade reactions, which result in rapid and efficient amplification of an organism's response to a physiological signal.

• https://en.wikipedia.org/wiki/Protease

Guillain-Barre: Protease Inhibitors.

• The activity of proteases is inhibited by protease inhibitors. One example of protease inhibitors is the serpin superfamily, which includes alpha 1-antitrypsin, C1-inhibitor, antithrombin, alpha 1-antichymotrypsin, plasminogen activator inhibitor-1, and neuroserpin.

• Natural protease inhibitors include the family of lipocalin proteins, which play a role in cell regulation and differentiation. Lipophilic ligands, attached to lipocalin proteins, have been found to possess tumor protease inhibiting properties. The natural protease inhibitors are not to be confused with the protease inhibitors used in antiretroviral therapy. Some viruses, with HIV/AIDS among them, depend on proteases in their reproductive cycle. Thus, protease inhibitors are developed as antiviral means.

• https://en.wikipedia.org/wiki/Protease

Guillain-Barre: Protease Inhibitors.

• Venoms.

• Certain types of venom, such as those produced by venomous snakes, can also cause proteolysis. These venoms are, in fact, complex digestive fluids that begin their work outside of the body. Proteolytic venoms cause a wide range of toxic effects, including effects that are:

• cytotoxic (cell-destroying)

• hemotoxic (blood-destroying)

• myotoxic (muscle-destroying)

• hemorrhagic (bleeding) https://en.wikipedia.org/wiki/Proteolysis#Venoms

Guillain-Barre: Protease Inhibitors.

• Inhibitors of Serine Protease.

• Inhibitors of Cysteine Protease.

• Inhibitors of Metallo-Proteases.

• Inhibitors of Aspartic Proteases.

Guillain-Barre: Protease Inhibitors.

• LITTLE is known about the mechanisms of carcinogenesis. The fact that most carcinogens are mutagenic has led to speculation that the primary step in cancer induction may be mutational; there is evidence from both in vivo and in vitro studies that a strong correlation exists between the mutagenicity and carcinogenicity of an agent. Mutagenic and carcinogenic agents, both physical and chemical, also produce similar kinds of DNA damage and repair.

• Radiation-induced mutagenesis in some bacterial cells requires an error-prone DNA repair system, and there is now some evidence that error-prone DNA repair may be involved in the malignant transformation of cells by radiation. Protease inhibitors have been shown to suppress specifically both error-prone repair and mutagenesis in bacterial cells , as well as to inhibit carcinogenesis in vivo .

• We report here that the protease inhibitors antipain and leupeptin will suppress radiation-induced transformation in vitro as well as inhibit two-stage transformation in vitro using radiation and the promoting agent, 12-O-tetradecanoyl-phorbol-13-acetate (TPA).

• Protease inhibitors suppress radiation-induced malignant transformation in vitro

• ANN R. KENNEDY & JOHN B. LITTLE

• Laboratory of Radiobiology, Department of Physiology, Harvard University, School of Public Health, Boston, Massachusetts 02115

Guillain-Barre: Protease Inhibitors.

• A lysosome (derived from the Greek words lysis, meaning "to loosen", and soma, "body") is a membrane-bound cell organelle found in most animal cells (they are absent in red blood cells). Structurally and chemically, they are spherical vesicles containing hydrolytic enzymes capable of breaking down virtually all kinds of biomolecules, including proteins, nucleic acids, carbohydrates, lipids, and cellular debris. They are known to contain more than 50 different enzymes, which are all optimally active at an acidic environment of about pH 5. http://en.wikipedia.org/wiki/Lysosome

Guillain-Barre: Protease Inhibitors.

• Cysteine proteases, also known as thiol proteases, are enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad. The first step in the reaction mechanism by which cysteine proteases catalyze the hydrolysis of peptide bonds is deprotonation of a thiol in the enzyme's active site by an adjacent amino acid with a basic side chain, usually a histidineresidue.

Guillain-Barre: Protease Inhibitors.

• Example of Inhibitors of proteases.

• http://iti.stanford.edu/content/dam/sm/iti/documents/himc/immunoassays/ProteaseInhibitionGuide.pdf

• Classes of Protease Inhibitors available from Roche Applied Science

Guillain-Barre: Protease Inhibitors.

Guillain-Barre: Protease Inhibitors.

• When isolating or purifying proteins, benefit from the ultimate in convenience – use complete Protease Inhibitor Cocktail Tablets and eliminate the time consuming search for the right protease inhibitor. complete is a proprietary blend of protease inhibitors, formulated as a ready-to-use water soluble tablet.

• Simply add the convenient tablet to your homogenization buffer, and instantly protect your proteins against a broad range of proteases.

• http://iti.stanford.edu/content/dam/sm/iti/documents/himc/immunoassays/ProteaseInhibitionGuide.pdf

Guillain-Barre: Protease Inhibitors.

• Consistently inhibit a multitude of protease classes, including serine proteases, cysteine proteases, and metalloproteases.

• Inhibit proteolytic activity in extracts from almost any tissue or cell type, including animals, plants, yeast, bacteria, and fungi.

• http://iti.stanford.edu/content/dam/sm/iti/documents/himc/immunoassays/ProteaseInhibitionGuide.pdf

Guillain-Barre: Protease Inhibitors.

• Deliver consistent doses of protease inhibition.

• Obtain stable, non-toxic protection in aqueous buffers.

• Maintain the stability of metal-dependent proteins, and function of purification techniques (i.e., IMAC [immobilized metal affinity chromatography] for isolation of Poly-His-tagged proteins) by using EDTA-free complete Protease Inhibitor Tablets.

• http://iti.stanford.edu/content/dam/sm/iti/documents/himc/immunoassays/ProteaseInhibitionGuide.pdf

Guillain-Barre: Protease Inhibitors.

• Some examples of cells, tissues, and organisms in which protease activity has been successfully inhibited with complete tablets — as reported in scientific literature:

• ■ Acintobacillus actinomycetemcomitans ■ Adipocytes (mouse, rat) ■Adrenal gland (PC-12, rat) ■ Bladder carcinoma cells (T24, human) ■Bone marrow cells (mouse, human) ■ Bone osteosarcoma (U-2 OS, SaOs-2, human) ■ Brain neuroblastoma cells (SK-N-BE(2), human) ■Brain tissue (bovine, mouse, rat, human) ■ Breast cancer cells (BT20, MCF7, human) ■ Bronchial Alveolar Lavage Fluid (mouse, rat)

Guillain-Barre: Protease Inhibitors.

• Bronchial Biopsies (human) ■ Bronchial epithelial cell line (BZR, human) ■ Cardiomyocytes (mouse, rat) ■ Cervix adenocarcinoma (HeLa, human) ■ Cochlea (rat) ■ Colon carcinoma cells (T84, human) ■ Colorectal adenocarcinoma cells (CaCo-2) (human) ■ Colorectal and duodenal adenomas ■ Colorectal carcinoma cells (HCT-116, human) ■Cortex (rat). ■ Dictyostelium (amoeba) ■ E. coli ■ Endothelial cell line ■ Epidermis (human) ■ Epithelial cell lines (human, bovine) ■ Fat (mouse) ■ Fibroblasts (human; NIH-3T3, MDTF, mouse) ■Fibrosarcoma cell line (HT1080, human) ■ Fruit (tomato) ■Glioblastoma cell line (U87MG) ■ Head (Drosophila).

Guillain-Barre: Protease Inhibitors.

• ■ Heart (human, mouse, chicken) ■ Hematopoietic cell lines (mouse, human) ■ Immature seed (soy) ■ Insect cell lines (Sf2, Sf21, Sf9, Tn5) ■ Keratinocytes (human) ■ Kidney (dog, human, mouse, rat, monkey, Xenopus) ■ Leaf (Arabidopsis) ■ Liver carcinoma cells (HepG2, Hep3B, human) ■ Liver tissue (mouse, rat, Xenopus) ■ Lung carcinoma cells (A549, human) ■ Lung homogenates (mouse, Xenopus) ■ Lung lavage fluid (mouse) ■ Luteal tissue (bovine) ■ Lymph nodes (mouse) ■Lymphoblastoids (human) ■ Lymphocytes (Jurkat, human; WEHI 3b D, mouse; monkey)

Guillain-Barre: Protease Inhibitors.

• ■ Peripheral blood cells (BA/F3, mouse; CEM, HL-60, human) ■ Pichia pastoris ■ Placental labyrinth (mouse, rat) ■ Platelets (human) ■ Primary chondrocytes (human) ■ Primary lung cancer cells ■ Primary mast cells (mouse) ■ Primary neuronal cultures (mouse) ■ Prostate adenocarcinoma cells (PC-3, human) ■ Prostate carcinoma cells (DU-145 and LNCaP, human) ■ Pseudomonas ■ Rectal tissue (rabbit).

• Renal cell carcinomas (human) ■ Reticulocyte lysate (rabbit) ■ Retina (mammalian) ■ Saccharomyces cerevisiae ■ Salivary gland (mouse) ■Salmonella typhimurium ■ Seed (Arabidopsis) ■ Skin (human) ■Spermatogenic cells (mouse) ■ Spinal cord (rat) ■ Spleen (mouse, rat, Xenopus) ■ Staphylococcus aureus ■ Streptococcus pneumoniae ■Superior cervical ganglion (mouse) ■ Toxoplasma gondii ■ Umbilical vein endothelial cells (HUVEC, human) ■ Whole plant tissue

Guillain-Barre: Protease Inhibitors.

• Mammary carcinoma cells (MDA468, human) ■ Mammary epithelial cells (HMEC) ■ Mammary gland (mouse) ■ Mast cell line (human) ■Monocyte cells (THP-1, human) ■ Muscle (Drosophila, human, mouse, rat, rabbit, Xenopus) ■ Neisseria gonorrhoeae ■ Neurons (rat) ■ Ovarian cancer (OVCAR-3, human) ■ Ovary cells (CHO, hamster) ■Pancreas (mouse) ■ Parathyroid tissue (bovine)

• http://iti.stanford.edu/content/dam/sm/iti/documents/himc/immunoassays/ProteaseInhibitionGuide.pdf

Guillain-Barre: Protease Inhibitors.

• USING PROTEASE BIOMARKERS TO MEASURE VIABILITY AND CYTOTOXICITY ANDREW NILES, MICHAEL SCURRIA2, LAURENT BERNAD, BRIAN MCNAMARA, KAY RASHKA, DEBORAH LANGE, PAM GUTHMILLER1 AND TERRY RISS , PROMEGA CORPORATION, PROMEGA BIOSCIENCES, INC.

Guillain-Barre: Protease Inhibitors.

• Guillain–Barré syndrome (GBS) is a rapid-onset muscle weakness as a result of damage to the peripheral nervous system. Many experience changes in sensation or develop pain, followed by muscle weakness beginning in the feet and hands. The symptoms develop over half a day to two weeks. During the acute phase, the disorder can be life-threatening with about a quarter developing weakness of the breathing muscles and requiring mechanical ventilation. Some are affected by changes in the function of the autonomic nervous system, which can lead to dangerous abnormalities in heart rate and blood pressure. https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome

•

Guillain-Barre: Protease Inhibitors

• This autoimmune disease is caused by the body's immune system mistakenly attacking the peripheral nerves and damaging theirmyelin insulation. Sometimes this immune dysfunction is triggered by an infection. The diagnosis is usually made based on the signs and symptoms, through the exclusion of alternative causes, and supported by tests such as nerve conduction studies and examination of the cerebrospinal fluid. Various classifications exist, depending on the areas of weakness, results of nerve conduction studies, and the presence of antiganglioside antibodies. It is classified as an acute polyneuropathy. https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome

Guillain-Barre: Protease Inhibitors.

• The first symptoms of Guillain–Barré syndrome are numbness, tingling, and pain, or in combination. This is followed by weakness of the legs and arms that affects both sides equally and worsens over time. The weakness can take half a day to over two weeks to reach maximum severity, and then becomes steady. In one in five people, the weakness continues to progress for as long as four weeks. The muscles of the neck may also be affected, and about half experience involvement of the cranial nerves which supply the head and face; this may lead to weakness of the muscles of the face, swallowing difficulties and sometimes weakness of the eye muscles.

• In 8%, the weakness affects only the legs (paraplegia or paraparesis).

• https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome

Guillain-Barre: Protease Inhibitors

• Involvement of the muscles that control the bladder and anus is unusual. In total, about a third of people with Guillain–Barrésyndrome continue to be able to walk. Once the weakness has stopped progressing, it persists at a stable level ("plateau phase") before improvement occurs. The plateau phase can take between two days and six months, but the most common duration is a week. Pain-related symptoms affect more than half, and include back pain, painful tingling, muscle pain and pain in the head and neck relating to irritation of the lining of the brain.

• https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome

Guillain-Barre: Protease Inhibitors.

• Many people with Guillain–Barré syndrome have experienced the signs and symptoms of an infection in the 3–6 weeks prior to the onset of the neurological symptoms. This may consist of upper respiratory tract infection (rhinitis, sore throat) or diarrhea.

• In children, particularly those younger than six years old, the diagnosis can be difficult and the condition is often initially mistaken (sometimes for up to two weeks) for other causes of pains and difficulty walking, such as viral infections, or bone and joint problems

• https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome

Guillain-Barre: Protease Inhibitors.

• On neurological examination, characteristic features are the reduced power and reduced or absent tendon reflexes (hypo- or areflexia, respectively). However, a small proportion has normal reflexes in affected limbs before developing areflexia, and some may have exaggerated reflexes. In the "Miller Fisher variant" subtype of Guillain–Barré syndrome (see below), weakness of the eye muscles (ophthalmoplegia) is more pronounced and may occur together with abnormalities in coordination (ataxia). The level of consciousness is normally unaffected in Guillain–Barré syndrome, but the Bickerstaff brainstem encephalitis subtype may feature drowsiness, sleepiness, or coma. https://en.wikipedia.org/wiki/Guillain%E2%80%93Barr%C3%A9_syndrome

Guillain-Barre: Protease Inhibitors.

• A quarter of all people with Guillain–Barré syndrome develop weakness of the breathing muscles leading to respiratory failure, the inability to breathe adequately to maintain healthy levels of oxygen and/or carbon dioxide in the blood.

• This life-threatening scenario is complicated by other medical problems such as pneumonia, severe infections,blood clots in the lungs and bleeding in the digestive tract in 60% of those who require artificial ventilation

Guillain-Barre: Protease Inhibitors.

• The autonomic or involuntary nervous system, which is involved in the control of body functions such as heart rate and blood pressure, is affected in two thirds of people with Guillain–Barré syndrome, but the impact is variable. Twenty percent may experience severe blood-pressure fluctuations and irregularities in the heart beat, sometimes to the point that the heart beat stops and requiring pacemaker-based treatment. Other associated problems are abnormalities in perspiration and changes in the reactivity of the pupils. Autonomic nervous system involvement can affect even those who do not have severe muscle weakness.

Guillain-Barre: Protease Inhibitors.

• he nerve dysfunction in Guillain–Barré syndrome is caused by an immune attack on the nerve cells of the peripheral nervous system and their support structures. The nerve cells have their body (the soma) in thespinal cord and a long projection (the axon) that carries electrical nerve impulses to the neuromuscular junction where the impulse is transferred to the muscle. Axons are wrapped in a sheath of Schwann cells that contain myelin. Between Schwann cells are gaps (nodes of Ranvier) where the axon is exposed.

Guillain-Barre: Protease Inhibitors.

• Different types of Guillain–Barré syndrome feature different types of immune attack. The demyelinating variant (AIDP, see below) features damage to the myelin sheath by white blood cells (T lymphocytes and macrophages); this process is preceded by activation of a group of blood proteins known as complement. In contrast, the axonal variant is mediated by IgG antibodies and complement against the cell membrane covering the axon without direct lymphocyte involvement

Guillain-Barre: Protease Inhibitors.

• Various antibodies directed at nerve cells have been reported in Guillain–Barré syndrome. In the axonal subtype, these antibodies have been shown to bind to gangliosides, a group of substances found in peripheral nerves. A ganglioside is a molecule consisting of ceramide bound to a small group of hexose-type sugars and containing various numbers of N-acetylneuraminic acid groups. The key four gangliosides against which antibodies have been described are GM1, GD1a, GT1a, and GQ1b, with different anti-ganglioside antibodies being associated with particular features; for instance, GQ1b antibodies have been linked with Miller Fisher variant GBS and related forms including Bickerstaff encephalitis

Guillain-Barre: Protease Inhibitors.

• The production of these antibodies after an infection is probably the result of molecular mimicry, where the immune system is reacting to microbial substances but the resultant antibodies also react with substances occurring naturally in the body.[1][12] After a Campylobacter infection, the body produces antibodies of the IgA class; only a small proportion of people also produce IgG antibodies against bacterial substance cell wall substances (e.g. lipooligosaccharides) that crossreact with human nerve cell gangliosides. It is not currently know how this process escapes central tolerance to gangliosides, which is meant to suppress the production of antibodies against the body's own substances.

Guillain-Barre: Protease Inhibitors.

• Not all antiganglioside antibodies cause disease, and it has recently been suggested that some antibodies bind to more than one type ofepitope simultaneously (heterodimeric binding) and that this determines the response. Furthermore, the development of pathogenic antibodies may depend on the presence of ofter strains of bacteria in the bowel

Guillain-Barre: Protease Inhibitors.

• 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.html

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

http://pubmedcentralcanada.ca/pmcc/articles/PMC3929455/

Guillain-Barre: Protease Inhibitors.

• 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

Guillain-Barre: Protease Inhibitors.

• 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

Guillain-Barre: Protease Inhibitors.

• 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

Guillain-Barre: Protease Inhibitors.

• Granzymes.