EP2941284A1 - Plasmaphérèse thérapeutique pour la galectine -3 - Google Patents

Plasmaphérèse thérapeutique pour la galectine -3

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Publication number
EP2941284A1
EP2941284A1 EP13830122.1A EP13830122A EP2941284A1 EP 2941284 A1 EP2941284 A1 EP 2941284A1 EP 13830122 A EP13830122 A EP 13830122A EP 2941284 A1 EP2941284 A1 EP 2941284A1
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European Patent Office
Prior art keywords
gal
cancer
inflammation
mammal
levels
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EP13830122.1A
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German (de)
English (en)
Inventor
Isaac Eliaz
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ELIAZ THERAPEUTICS, INC.
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Eliaz Therapeutics Inc
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Publication of EP2941284A1 publication Critical patent/EP2941284A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
    • A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
    • A61M1/3496—Plasmapheresis; Leucopheresis; Lymphopheresis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Galectins are a family of lectins (sugar binding proteins) that are characterized by having at least one carbohydrate recognition domain (CRD) with an affinity for beta-galactosides. These proteins were recognized as a family only recently, but are found throughout the animal kingdom, and are found in mammals, birds, amphibians, fish, sponges, nematodes and even fungi. This application focuses on galectins in mammals, and in particular, humans. Although the invention herein may be employed with both companion animals (e.g.. pets such as dogs and cats) and commercial animals (such as cows, pigs and sheep) the methods and subject matter addressed herein are particularly focused on the treatment of humans.
  • companion animals e.g.. pets such as dogs and cats
  • commercial animals such as cows, pigs and sheep
  • Galectins mediate and modulate a wide variety of intracellular and extracellular functions, and thus are both expressed within the cell and frequently targeted to a specific cytosolic site, and secreted from the cell, for distribution extra-cellularly, as a component of human plasma.
  • functions that are mediated by extracellular galectins are inflammation, fibrosis formation, cell adhesion, cell proliferation, metastatic formation, angiogenesis (cancer) and immunosuppression.
  • Galectins are a family of fifteen (15) carbohydrate -binding proteins (lectins) highly conserved throughout animal species. Most galectins are widely distributed, though galectin -5, -10 and -12 show tissue-specific distribution. While galectins are variably expressed by all immune cells, they are upregulated in activated B and T cells, inflammatory macrophages, natural killer (NK) cells, and FoxP3 regulatory T cells. Galectins contain a variety of structural arrangements, but a relatively conserved carbohydrate recognition domain (CRD).
  • CCD carbohydrate recognition domain
  • galectins display a single CRD, and are biologically active as monomers (galectin-5,-7 and -10), or require homodimerization for functional activity (galectin- 1,-2,- 11,-13,-14 and-15).
  • tandem-repeat-type galectins (galectin-4,-8,-9, and -12) contain two CRDs separated by a short linker peptide, while galectin-3 (chimeric type) has a single CRD fused to a non-lectin domain that can be complexed with other galectin-3 monomers to form an oligomeric pentamer.
  • galectins such as galectin- 10, bind to mannose-containing glycans.
  • galectins -1, -3, and -9 are particularly important as potential therapeutic targets, and -2,-4,-5,-6,-7,-8,-10, -11,-12,-13,- 14, and -15 also appear implicated in a variety of biological pathways associated with morbidity and mortality.
  • galectin-7 has been implicated in the development of certain forms of cancer. St. Pierre et al, Front. Biosci., 1 : 17, 438-50 (2012) and in a variety of specific cancers, including gal-2, -4 and -8 in the context of colon and breast cancer, Barrow et al, Clin. Cancer Res,. 15; 17 (22) 7035-46 (2011). Squamous cell carcinoma of the tongue, Alves et al., Pathol. Res. Pract. 15;207 (4) 236-40 (2011) has been shown to be associated with elevated levels of gal-1, -3 and -7, while cervical squamous carcinoma has been shown linked to gal-7 levels, Zhu et al, Int. J.
  • galectins including gal- 15, gal- 13 and gal- 10 have been demonstrated to be linked to implantation and pregnancy concerns. See, e.g.. Than et al, Eur. J. Biochem. 271(6) 1065-78 (2004), Lewis et al, Biol. Reprod. 77(6); 1027-36 (2007).
  • a number of galectins, including gal-2, 3, 8 and others have been identified as correlating with various autoimmune disorders, such as lupus. Salwati et al, J. Infect. Dis. 1;202(1) 117-24 (2010), Pal et al, Biochim. Biophys. Acta.
  • galectins critical elements of a wide variety of disease, injury and trauma related phenomena. In many cases, the presence of unwanted concentrations of galectins can aggravate a disease condition or trauma situation, or interfere with attempts to treat diseases, such as cancer or congestive heart failure.
  • galectin-1, galectin-3 and galectin-9 are of particular interest. As indicated above, these proteins are generally referred to, and referred to herein as, gal-1, gal-3 and gal-9.
  • Gal-3 is particularly prominent in fibrosis, inflammation and cell proliferation, while gal-1 also plays a role in the immunosuppression required for a successful pregnancy.
  • Gal-1 is also thought to be involved in the differentiation of nerve cells.
  • Gal-9 has been shown to be involved in the control of lesions arising from immunoinflammatory diseases, and is generally implicated in inflammation - gal-9 apparently plays a role in eosinophil recruitment in inflammatory sites. It also appears to mediate apoptosis in certain activated cells.
  • binding and blocking activity of gal-3 in the circulation, or removal of large amounts of gal-3 from circulation may therefore improve existing medical treatments, suppress and/or reduce inflammation and fibrosis resulting from others, and make it possible to intervene in various disease states not otherwise easily treated.
  • the invention is equally applicable to the reduction in circulating levels of other active galectins to address conditions mediated by those galectins.
  • active galectins what is referred to is biologically active molecules.
  • gal-3 can be active, that is, mediate mammalian responses to various traumas and conditions, as a monomer and as an oligomer.
  • gal-3 and other galectins are present in an inactive state - that is, they are either tissue bound or ligand bound in such fashion as to inhibit molecular interaction. While such galectins molecules may become active, and may be or become the target of removal by the invention disclosed herein, when monitoring patient conditions and controlling responses, the focus of the invention is the removal of active galectins from the blood stream.
  • This invention makes use of plasmapheresis, sometimes referred to as therapeutic plasma exchange, to control levels of gal-3, and more specifically biologically active galectin, in circulation.
  • Plasma is lead through a fluid pathway and either intermixed with a gal-3 binding agent which can be separated from the plasma, or returned to the body with blocked inactivated gal-3, or lead past a solid support which binds gal-3, the plasma being subsequently returned to the body with a reduced level of gal-3.
  • this invention can be used to remove bound gal-3 as part of a strategy to reduce total gal-3 content.
  • the focus, in this application, however, is to remove active or unbound gal-3 as a therapeutic measure.
  • Gal-3 is approximately 30 kDa and, like all galectins, contains a carbohydrate- recognition-binding domain (CRD) of about one hundred thirty (130) amino acids that enable the specific binding of ⁇ -galactosides.
  • Gal-3 is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. This protein has been shown to be involved in a large number of biological processes. The list set forth herein is exemplary only as new situations and roles for gal-3 are continually being revealed.
  • gal-3 Given gal-3 's broad biological functionality, it has been demonstrated to be involved in a large number of disease states or medical implications. Studies have also shown that the expression of gal-3 is implicated in a variety of processes associated with heart failure, including myofibroblast proliferation, fibrogenesis, tissue repair, inflammation, and ventricular and tissue remodeling. Elevated levels of gal-3 in the blood have been found to be significantly associated with increased morbidity and mortality. They have also been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations.
  • Inflammation is a commonly encountered body condition - a natural response of the body to a variety of diseases and trauma.
  • gal-3 levels above normal levels are implicated in a wide variety of situations where harmful inflammation is encountered.
  • inflammatory conditions associated with elevated gal-3 levels include aggravated inflammation associated with non-degradable pathogens, autoimmune reactions, allergies, ionizing radiation exposure, diabetes, heart disease and dysfunction, atherosclerosis, bronchial inflammation, intestinal ulcers, intestinal
  • ALS amyotrophic lateral sclerosis
  • Gal-3 is also involved with kidney injury and kidney disease, hepatitis, pulmonary hypertension and fibrosis, diabetes, and gastrointestinal inflammatory conditions such as ulcerative colitis, Crohn's disease, celiac disease, and others.
  • Plasmapheresis is a blood separation technology, where blood is diverted from the body through a needle or catheter to a separator which removes blood cells and returns them to the body, leaving plasma.
  • This type of technique has been used historically in the treatment of autoimmune diseases, where the antibodies at issue are removed by contacting the plasma with the ligands to which they bind. The plasma is then augmented as required, with anticoagulants, therapeutics and associated elements, and returned to the body.
  • plasma exchange or replacement therapies generally, as illustrated in U.S. patent publication US 2006/0129082, the technology was used to target and remove "toxic serum components" such as ammonia, uric acid, and cell growth inhibitors.
  • this invention reflects the first use of plasmapheresis to lower and control the level of active gal-3, an essential and relatively low molecular weight molecule, to support patients in specific need of hat relief.
  • U.S. Patent Nos. 6,245,038 and 6,627,151 each describe a variety of methods of separating out plasma contents and returning the treated plasma to the patient after first removing red blood cells, in general, to reduce blood viscosity by removal of high molecular weight protein. While the invention that is the subject of this application focuses on the reduction in galectins circulating levels, such as gal-3 levels, and not high molecular weight proteins or directly addressing viscosity, the disclosure of these four (4) patents is incorporated herein-by-reference for their disclosure of available plasmapheresis techniques and apparatus which may generally be employed in this invention.
  • Gal-3 binders such as MCP and other compounds can bind to circulating tumor cells (CTC's) and prevent them from creating new metastasis. These CTC's are often implicated in mutations and a more aggressive disease. Cancer stem cells that may also be circulating and get stimulated under conditions of stress and inflammation, provide gal-3 another mechanism for aggravating cancer. The method of these prior cases may be used in conjunction with the invention of this application. In particular, when there are a high number of gal-3 molecules circulating in the blood stream it makes it more difficult for the gal-3 binders to target these CTCs. In this respect, gal-3 molecules serve as decoy molecules. The decoy prevents, in this particular application of the invention, binding of the cancer cells in the circulatory or lymph system, as opposed to tissue level gal-3.
  • Circulating gal-3 is empirically implicated in a wide variety of biological conditions, however. Cardiac fibrosis is gaining significant attention as a complicating risk factor in cardiac disease, and in particular, chronic heart failure (CHF). Lok et al, Clin. Res. Cardiol, 99, 323-328 (2010). DeFillipi et al, U.S. Cardiology, 7, 1, 3-6 (2010) clearly indicate that circulating gal-3 is an important factor in fibrosis of many organs and organ systems, and that reducing circulating gal-3 may have an important role in remediating cardiac injury and progression to heart failure (HF). Similarly, Psarras et al, Eur. Heart J.
  • Inflammation is the hallmark of arteriosclerosis and therefore gal-3 levels also contribute to coronary artery disease, peripheral artery disease, strokes, and vascular dementia.
  • Fibrosis and inflammation are implicated in a variety of conditions of the mammalian body, not just cardiac injury and heart failure.
  • the binding of gal-3 achieved by administration of low molecular weight pectins (at least, as reflected in U.S. Patent Application Serial No. 11/485,955, 10,000-20,000 Daltons molecular weight such as MCP) is effective in reducing trauma due to kidney injury.
  • Reducing circulating gal- 3 levels may be effective in reducing fibrosis in the lungs and associated asthma.
  • gal-3 is implicated in a wide variety of biological conditions, and a reduction in gal-3 activity, such as that which can be achieved by gal-3 binding with MCP and similar low molecular weight pectins may be of value in treating gastric ulcerative conditions.
  • Kim et al, Gastroenterology, 138, 1035-45 (2010) indicate that reducing gal-3 levels may be of therapeutic value in reducing gastric cancer progression.
  • reducing gal-3 levels sensitizes gastric cancer cells to conventional chemotherapeutic agents. Cheong et al, Cancer Sci., 101, 1, 94-102 (2010).
  • Gal-3 is implicated in a wide variety of gastrointestinal conditions.
  • Reducing gal-3, by binding for example, may reduce inflammation in the gut mucosa, making MCP an important agent for treatment of ulcerative colitis, non-specific colitis and ileitis, Crohn's disease, Celiac disease, and gluten sensitivity.
  • MCP an important agent for treatment of ulcerative colitis, non-specific colitis and ileitis, Crohn's disease, Celiac disease, and gluten sensitivity.
  • Biliary artesia a liver disease, is associated with extensive fibrosis of the liver linked with elevated gal-3 levels. Honsawek et al, Eur. J. Pediatr. Surg. , April, 2011.
  • MCP may be used for prevention of liver inflammation, liver fibrosis and liver cirrhosis as well as post-disease liver damage, including the various viral hepatitis diseases (A, B, C, and others) and may be used as well in the treatment of parasitic and chemical hepatitis, chemical liver damage, and others.
  • Gal-3 levels are implicated in a wide variety of liver associated ailments. Thus, gal-3 may be important in the control of Niemann-Pick disease type C, which is a lysosomal disorder characterized by liver disease and progressive neurodegeneration. Cluzeau et al, Hum. Mol. Geent. 14; 21 (16) 3632-46 (2012). There is increasing evidence that elevated gal-3 levels are tied to acetaminophen-induced hepatotoxicity and inflammation. Radosavljeci et al, Toxicol.
  • gal-3 blockers such as MCP, and possibly other oligo-saccharides and various pharmaceutical agents to be developed to better attach to the gal-3 on the cell surface and on the tissue level.
  • the gal- 3 binding agent can more effectively bind to the gal-3 in the target tissue.
  • the invention resides in the removal of biologically active gal-3, as well as biologically active problematic galectins, such as gal-1 and gal-9, from a mammal's circulation by apheresis of one type or another.
  • the invention is generally applicable to removal of any galectin which mediates biological phenomena such as autoimmunity and cell proliferation (gal-9 and -1, respectively), such that their removal can support or improve therapies already in existence .
  • the mammal may be a human, a primate, a model such as a rat or mouse, a commercial animal such as a cow or pig or goat, or a companion animal such as a dog or cat.
  • Non-human mammalian animals for treatment include primates, both as models and as test beds for treatments and intervention that may benefit from removal of gal-3 from circulation. Removal is achieved by plasmapheresis, a process traditionally developed and used to remove antibodies from the circulation of those suffering from autoimmune disorders and the like.
  • Apheresis is defined as a procedure in which one of the components of blood is removed.
  • Plasmapheresis of course addresses removal of plasma.
  • Therapeutic apheresis is a process in which whole blood is removed from a patient and separated into components, thus allowing a single element to be removed or modified while the remaining components are returned to the patient.
  • the aim of one form of plasmapheresis also known as therapeutic plasma exchange (TPE)
  • TPE therapeutic plasma exchange
  • This may be the patient's plasma following treatment of some type, such as removal of gal-3 from that plasma, or a plasma substitute that is galectin free.
  • TPE differs slightly from donor apheresis, which is used to collect platelets, granulocytes, or peripheral blood stem cells from normal individual donors.
  • the volume of blood to be exchanged is based on a kinetic model of an isolated one-compartment intravascular space, which assumes that the component is neither synthesized nor degraded during the procedure and that it remains within the intravascular compartment.
  • the time interval between plasma exchanges is generally chosen based on the need to allow the component of interest to re-equilibrate into the intravascular space and the need to minimize the risk of bleeding as a result of dilutional coagulopathy.
  • GVHD graft versus host disease
  • drug toxicities as explained, infra, it may be preferred to perform a plasma exchange introducing amounts of exogenous plasma, or exogenous isotonic solutions such as normal saline, with or without albumin and other components, to increase benefits of lowering gal-3 in an expeditious manner and to reduce complications. Since removing gal-3 more rapidly than it can be renewed in the body is of importance, the need to decrease time between intervals of gal-3 lowering plasmaphersis may also lend itself to more efficacious therapy if the replacement therapy includes an amount of replacement plasma in the process to maintain low levels of gal-3 in the serum. With the inclusion of plasma exchange into the procedure, any circulating pathogens and toxins can also be reduced in individuals with these concerns.
  • Plasma exchange allows for removal of other components that have detrimental effects, and can therefor contribute to the efficacy of the therapy.
  • immune inhibitory components that circulate in the plasma.
  • TNF alpha receptors that can be present at elevated amounts in the blood stream of cancer patients.
  • TPE the patient's plasma is removed from the blood by centrifugation or a cell separator/filter and is replaced with saline, albumin, and/or fresh frozen plasma (FFP), thus maintaining volume and oncotic equilibrium.
  • FFP fresh frozen plasma
  • An anti-coagulant is added to the blood to help avoid clotting. The procedure must be controlled to ensure that the patient is kept in fluid balance, maintaining a stable, normal plasma volume.
  • Additional laboratory testing such as fibrinogen, ESR, PT/PTT (INR) and comprehensive metabolic panel may also be used to assess the patient.
  • the efficacy of the therapy and treatment interval regimen is assessed by these values when compared to post therapy levels.
  • high-flow automated devices (1) are primed to allow for removal of all air from the circuit and maintenance of the patient's volume, (2) require venous access for inflow to the machine and blood return to the patient, (3) have a significant extracorporeal volume, which approaches 500 mL for adult configurations, and (4) are programmable with patient sex, height, weight, and hematocrit and permit blood to be monitored by a marker (e.g. gal-3).
  • a marker e.g. gal-3
  • plasmapheresis blood is removed from the patient, and blood cells are separated out from the plasma.
  • the blood cells are returned to the body's circulation, diluted with fresh plasma or a substitute.
  • Conventional plasmapheresis methods include medications that can include blood thinners as necessary.
  • the plasma is run over proteins to which the target antibodies bind, in this particular case, the plasma is returned to the blood with the antibodies, cytokines, lymphocytes and other blood components, after having had gal-3 selectively removed or inactivated by contact with gal-3 binding molecules.
  • the removal of gal-3 from the plasma can be an adjuvant therapy added to the traditional plasmapheresis performed for such patients.
  • Other cytokines and plasma components may be removed in the process, based on the specific condition and the specific individual.
  • This treatment may be used for all the conditions where galectin, including gal-3, levels are elevated in the blood or serum or where expression of gal-3 in the tissues is too high. Tissues will shed excess gal-3 into the blood stream where it can be removed through this invention.
  • Treatment can be varied depending on the patient, the severity of the condition and the rate of the mammalian patient's expression of gal-3. Ordinarily, treatment every two to four weeks is contemplated until the condition is resolved, but treatment may be daily where required, or at any frequency there between. Daily treatment includes one or more plasma exchange sessions in a given day, or continuous plasmapheresis over a multiple hour period in acute conditions. This may be particularly the case where there has been a build-up of gal-3 levels in the tissues of the patient being treated.
  • GCS is a polysaccharide derived from MCP, as opposed to reduced MCP.
  • a large variety of gal-3 binding antibodies are commercially available, from suppliers including abeam (ab2473), Novus Biologies (NB 100-91778) and Abgent (AJ13129). Other galectins-3 specific antibodies may be used.
  • soluble TNF receptors both R- 1 and/or R-2 at different ratios based on the condition, are removed, through the same process, by running the plasma fluid over a bed of binding agents of TNF receptors. TNF can then directly target cancer cells or other targets as an effective treatment.
  • the reduction of active gal-3 in both the circulation and the tissue level will allow TNF to exert its beneficial effects with a reduced amount of inflammation and fibrosis which limits its use. Wu et al, Arch. Dermatol. 20: 1-7 (2012).
  • the effective removal of serum gal-3 also enhances chemotherapy, particularly, but not exclusively, when combined with TNF receptor removal. Chemotherapy enhancement will take place by effective removal of serum gal-3, reducing drug resistance, even if no TNF receptors were removed from the circulation.
  • Gal-3 interferes with platinum-based chemotherapy and other anti-cancer agents, and increases cell adhesion, and angiogenesis. Wu et al, Cell Oncol. 35(3): 175-80 (2012).
  • removal of gal-3, by plasmapheresis alone, or together with administration of circulating gal-3 binders like low molecular weight MCP may effectively treat the diseases and conditions addressed above. In addition, this can be further enhanced by combining it with other therapies, one example being chemotherapy in cancer.
  • Typical circulating gal-3 level averages for a Caucasian adult range from 7 on up to about 20 ng/ml, with a value of 12-15 nanograms of gal-3 per milliliter of serum being a representative and reported value.
  • individuals facing serious illness or continued disability due to gal-3 mediated fibrosis, gal-3 mediated inflammation, and cancer growth, transformation and metastases associated with elevated gal-3 levels are treated by plasmapheresis to achieve a significant reduction in circulating gal-3 titer.
  • the gal-3 levels in races other than Caucasians and subjects may vary, but the target is to reduce gal-3 levels below the appropriate normal value. Target levels can vary based on the condition, age, gender, and other therapies involved.
  • treatment of the patient according to this invention may begin with plasmapheresis in conjunction with the absorptive column designed to reduce the patient's gal-3 to a preselected value consistent with good health and homeostasis in that individual. In some cases, it may be necessary to repeat or extend that treatment to achieve even greater reductions.
  • This invention is straightforward in its application. It is recognizing how many different indications are served by this technology that is complex and startling.
  • blood is removed from the patient according to well established protocols generally used for plasmapheresis. See, generally, Samuels et al, editors, Office Practice of Neurology, 1996.
  • the removed blood is treated to remove blood cells from the plasma. These blood cells, together with an additional volume of plasma or plasma substitute, are returned directly to the patient.
  • two to four liters of plasma may be removed, filtered, and replaced.
  • the blood can also be recycled and recirculated extra corporally, and filtered as needed, for a number of times (continuously) until the desired reduction in serum levels of galecitn-3 is achieved.
  • the blood cell-depleted plasma is then introduced to a chamber where gal-3 is removed or inactivated by binding antagonist, possibly creating a permanent bond that inactivates the gal-3.
  • binding antagonist possibly creating a permanent bond that inactivates the gal-3.
  • One of two alternative measures may be used to remove gal-3, although they may be combined.
  • the plasma is admixed with a particle which binds gal-3.
  • this is an antibody or similar ligand, or a polysaccharide derivative that is most preferably MCP, but any agent that can bind gal-3 can be used.
  • adsorbent galectin affinity columns can be prepared with matrix linked compounds having multivalent presentation of galactose, lactose, poly-N-acetyllactosamine, N acetyl-D-lactosamine, lacto-N-tetraose, lacto-N- hexosespecific peptides, aptamers (oligonucleic acid or peptide molecules), oligosaccharides, glycoproteins (such as alpha-2 macroglobulin and haptoglobulin), antibodies, engineered Fc (fragment, crystallizable) and Fab (fragment antigen binding) antibody fragments, Thomsen-Friedenreich glycoantigen (TFAg) or with small carbohydrate
  • the binding agent is modified to be complexed with an agent that is easily removed.
  • this is a magnetic particle.
  • a magnetic field is applied to the fluid comprising the plasma and the MCP complex, and the bound gal-3 can be drawn off.
  • Different filters that incorporate gal-3 binders can be used in the plasmapheresis process.
  • the circulating gal-3 can be viewed as a sort of decoy released by the cancer cells. It has a protective quality as it doesn't allow the host, and doesn't allow gal-3 binders such as MCP to reach the target tissue where galecin-3 is over expressed. It also induces inflammation and fibrosis and makes it more difficult for the host to bind to the gal-3 in the tissue and cell surface level. Removing the circulating gal-3 provides both a therapeutic treatment on its own and allows other agents to bind and inactivate the gal-3 in the target tissue level. This is similar to TNF Alpha and circulating TNF alpha receptors.
  • Such plasmapheresis can be combined with plasmapheresis of other compounds, and can enhance an immune response and an anti -inflammatory response.
  • the reduction of circulating gal-3 will allow one of skill in the art, typically a medical practitioner with at least five (5) years of experience in the field in addition to appropriate educational experience, to more easily neutralize and inactivate the tissue expressed gal-3, thus allowing for a local immune response with less inflammation and fibrosis.
  • it can be combined with removal of TNF Alpha receptors, both R-l and R-2. It can also be combined with administration of TNF alpha or agents that enhance TNF alpha activity.
  • Removing or reducing the level of circulating gal-3 can reduce the systemic and unwanted inflammatory process, resulting, as demonstrated in the kidney MCP study, with reduction in levels of IL-6, and consequently TNF alpha and TNF kappa beta.
  • B Reduction of secondary pro-inflammatory cytokines such as IL-6, TNF alpha, TNF kappa beta, and others.
  • the gal-3 comprising plasma may be run past a solid phase of immobilized gal-3 binding agents.
  • MCP is one example and gal-3 specific antibodies, bound to a column or tube, are another.
  • these two approaches to removal of gal-3 from circulation are combined. They can be combined in either order, but running the plasma past an immobile phase, followed by combining the plasma with an easily removable binding agent is preferred.
  • the binding of an antagonist to gal-3 may be adequate to inactivate the molecule, and thus can be returned to the body without the step to remove it from the plasma.
  • the binding of gal-3 by a plasmapheresis element that will remove it from circulation is an event that will aid medical conditions over a wide variety of indications.
  • the indications are principally associated with inhibiting tumor growth and transformation (cancer), inflammation and fibrosis and enhancing innate immune capacity.
  • Elevated circulating gal-3 can change a localized situation, such as localized inflammation or fibrosis, and convert it into a larger, systemic problem.
  • gal-3 binds to components in the blood, which also bind toxic agents and the like, or similarly, when localized toxins are bound by gal-3, the damage potentially caused by these agents proximate to a localized injury or diseased tissue can become systemic.
  • Gal-3 is a generally adhesive molecule. Elevated gal-3 levels will accelerate the spread of cancer from a localized tumor to a system wide, multi-organ problem. Reducing elevated gal-3 levels below 15 or 12 ng/ml, by ten percent (10%) or more, will help to localize injury and damage, and maximize the benefit of unrelated therapeutic agents at the local injury or disease site.
  • elevated gal-3 levels are associated with growth, transformation, angiogenesis and metastatic migration of cancer cells across a wide variety of cancers, including liver cancer, kidney cancer, breast cancer, prostate cancer, colon cancer, thyroid cancer, cancer of the gallbladder, nasopharyngeal cancer, lymphocytic leukemia, lung cancer, melanoma, multiple myeloma, glioblastoma multiforme, uterine cancer, ovarian cancer, cervical cancer, and brain cancer among others, as well as reducing sensitivity in these cancers to conventional antineoplastic agents.
  • Elevated gal-3 levels are also associated with the development and extension of fibroses beyond normal and healthy levels, in situations associated with cardiovascular disease and heart failure, in tissue injury including brain, lungs, renal, hepatic, heart and gastroenterological situations as well as tissue damage due to radiation and chemotherapy exposure.
  • Above-normal gal-3 levels are also encountered in connection with inflammation.
  • This can be disease or trauma associated inflammation, as well as persistent acute inflammation due to non-degradable pathogens, persistent foreign bodies, or autoimmune reactions, hypersensitivities and allergies, ionizing radiation, nuclear radiation and inflammation that may be associated with disease or organ failure modes, including diabetes (I and II), heart disease and dysfunction, atherosclerosis, asthma (bronchial inflammation), gastric and duodenal ulcers, intestinal inflammation in the bowels (inflammatory bowel diseases), hepatic inflammation associated with both alcohol and non-alcohol related cirrhosis and inflammation, liver infections such as viral hepatitis, among others.
  • ⁇ indications associated with inflammation and susceptible to treatment by plasmapheretic treatment to reduce gal-3 levels include a variety of parasite-induced conditions, such as trypanosomiasis, cerebral malaria, and inflammation and resistance to various infections including Paracoccidiosis brasilensis (fungal infection), schistosomiasis, granulatomatous bronchopneumonia, Lyme disease, tubercolosis, etc.
  • Reports of elevated gal-3 levels in connection with infection include Candida albicans, Reales-Calderon et al, J. Proteomics, 3:75(15) 4734-46 (2012), Schistoma mansoni ( a parasitic infection) Brand et al, Histol.
  • Gal-3 has been shown in multiple studies to contribute to the ability of tumors to evade the immune system.
  • Tumor cells secrete gal-3 into the tumor micro environment where the gal-3 via its self-adherent properties has a cloaking effect on cancer cells, effectively preventing immune cells from interaction with the antigens present on the surface of tumor cells.
  • These immune cells including CD4 and CD8 tumor infiltrating T lymphocytes, as well as macrophages, are thus suppressed in their capacity to be activated by tumor cell surface antigens; Immune suppression can occur because gal-3 also binds directly to immune cells (lymphocytes and macrophages) or traps and effectively immobilizes them in a glycoprotein matrix in the tumor microenvironment.
  • These immune cells are found in the tumor microenvironment in response to antigens that are present on the surface of tumor cells.
  • Activation of the immune system by reduction of gal-3 is a further aspect of the invention. Inhibition of gal-3 has been found to enhance the proliferation of immune cells in response to antigens presented on tumor cells. Demotte N, et al, Immunity. 28(3):414-24 (2008). Rapid systemic removal of gal-3 could be used in conjunction with oral gal-3 antagonists to exponentially enhance the effect of freeing the immune system to effectively act on tumor cells. This enhanced response via systemic removal of gal-3 can be used in conjunction with a number of immune enhancing therapies currently available or being developed.
  • Galectins have been documented as main regulators of immune cell homeostasis and inflammatory processes. Among these, gal-3 with its anti-apoptotic activity has been reported that increased gal-3 expression correlates with defective T-cell apoptosis in patients with some immune disorders. The level of gal-3 in patients receiving allogeneic
  • HSCT hematopoietic stem transplantation
  • GVHD acute graft- versus-host disease
  • Inflammation mediated at least in part by circulating gal-3 levels also plays a role in organic psychiatric and brain disorders. This kind of inflammation has been associated with a wide variety of conditions, such as schizophrenia. Muller et al., Adv. Protein Chem Struct. Biol , 88, 49-68 (2012) and Palladino et al, J. Neuroinflammation, 22;9, 206 (2012). Thus, reducing elevated gal-3 levels may be one method to assist in the control of psychiatric disorders of this type which are difficult to control by therapeutic intervention alone.
  • ADHD attention deficit hyperactivity disorder
  • Gal-3 has also been shown to be involved in the proper differentiation of oligodendrocytes controlling myelin sheath conditions, Pasquin et al, Cell Death Differ., 18(11), 1746-56 (2012) and recovery and regrowth following traumatic brain injury. Venkatesan et al, J.
  • inflammation and fibrosis can be induced by deliberate treatment, not just trauma or disease condition.
  • the removal of circulating, unbound gal-3 through this invention can be effective in reducing or preventing organ damage induced by chemotherapy and other pharmaceuticals.
  • Some examples include bleomycin, which induces lung fibroses, and a wide variety of cardiac drugs such as amiodarone. Adriamycin and doxorubicin are widely prescribed and present cardiac inflammation and fibroses issues.
  • Bacillus Calmette-Guerin washes to treat bladder cancer induce systemic inflammation and cyclophosphamide also induces bladder damage.
  • Cyclosporine a widely used immunosuppressant drug, and the active agent in Restasis TM , induces kidney toxicity and inflammation.
  • nonalcoholic steatohepatitis NASH
  • Sepsis See Bibhuti et al, 2013
  • post-trauma nerve regeneration NASH
  • DXR delayed xenograft rejection
  • IRI Ischemic- reperfusion injury
  • IPF Ideopathic pulmonary fibrosis
  • the use of at least partial donor-provided apheresis to reduce active Gal-3 levels in a patient may find particular application in the treatment of chronic kidney infection and end stage renal disease.
  • CKD chronic kidney infection
  • 800,000 individuals with Stage 4 CKD the number of these patients is expected to double by 2020.
  • Patients with Stage 4 CKD have a -10% death rate and the first-year death rate for ESRD patients is -25%.
  • the serum, after having circulating gal-3 reduced or removed, as described, is further treated before returning it to the patient's blood stream.
  • agents that may be more effective in the absence of, or in the presence of reduced levels of, galectin-3 are specifically added.
  • an anti-inflammatory will work better, cardiac medications, any drugs delivered to address an issue where gal-3 is a contributing factor, or prevents effective delivery to the target tissue, will be enhanced by this process.
  • the invention involves long term or chronic plasmapheresis to maintain reduced gal-3 levels
  • the invention also contemplates intervention on a short term basis, both removing circulating gal-3 and providing agents otherwise inhibited by gal-3, to swiftly address inflammation in particular.
  • Gal-3 levels can spike as a transient event, in response to trauma for example, having a technique to rapidly lower gal-3 levels in the patient, coupled with administration of active agents that are ordinarily inhibited to some degree by high levels of gal-3, can offer a lifesaving technique.
  • reducing Gal-3 levels as a means to reduce inflammation can allow other therapeutic agents, an example being an anti microbial in acute infections such as sepsis, or others, to have a better therapeutic response, resulting in a life saving outcome.
  • Asthma, and related conditions primarily marked by exaggerated inflammation may be avoided or suppressed by removing circulating gal-3 through the process of this invention. These include inflammation of the gastrointestinal tract, and inflammation and the development of fibroses of the liver, interstitial cystitis, inflammation associated with brain and cognitive function, and others. Inflammation associated with parasite invasion may also be controlled by removal of gal-3, or reducing its circulating level through this invention. Other inflammation-associated diseases, such as diabetes and arthritis are similarly treated. These conditions may ideally be targets of this invention as well as administration of circulating gal-3 binding agents like MCP, and unrelated therapeutic agents.

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Abstract

L'invention concerne l'élimination de la gal-3 sérique de la circulation par plasmaphérèse, comprenant au moins en partie une aphérèse donneur, à l'aide d'agents se liant à la gal-3 dans un lit fixe, ou sous une forme facile à éliminer, comme lorsqu'elle est complexée avec des particules magnétiques. Cette méthode, à elle seule, apporte une forte réduction et un fort soulagement de l'inflammation et des fibroses qui peuvent être induites par la gal-3 en circulation. La méthode peut être combinée à l'administration d'agents se liant à la gal-3, tels qu'une pectine d'agrume modifiée, pour réduire davantage les taux de gal-3 non liée, jusqu'au point où la gal-3 dans les tissus n'est plus un problème. Cette méthode peut également être combinée à l'élimination des récepteurs du TNF pour obtenir un traitement efficace contre le cancer.
EP13830122.1A 2013-01-07 2013-12-27 Plasmaphérèse thérapeutique pour la galectine -3 Withdrawn EP2941284A1 (fr)

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JP2024526764A (ja) * 2021-07-13 2024-07-19 トゥルーバインディング，インコーポレイテッド タンパク質凝集を防止する方法
US20230123338A1 (en) * 2021-10-16 2023-04-20 Isaac Eliaz Apheresis of whole blood
US20250135079A1 (en) * 2023-10-30 2025-05-01 Eliaz Therapeutics, Inc. Method for Treating Sepsis

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AU2013371859B2 (en) 2018-06-21
WO2014106803A1 (fr) 2014-07-10
MY168406A (en) 2018-11-07
AU2016262697A1 (en) 2016-12-15
AU2016262697B2 (en) 2018-06-28
MY179276A (en) 2020-11-03
IL239448A0 (en) 2015-07-30
AU2013371859A1 (en) 2015-07-16
CA2893690A1 (fr) 2014-07-10

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