WO2008115569A1 - Procédé pour inhiber les réponses immunitaires chez les mammifères utilisant des mutéines de ligand fas - Google Patents

Procédé pour inhiber les réponses immunitaires chez les mammifères utilisant des mutéines de ligand fas Download PDF

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Publication number
WO2008115569A1
WO2008115569A1 PCT/US2008/003714 US2008003714W WO2008115569A1 WO 2008115569 A1 WO2008115569 A1 WO 2008115569A1 US 2008003714 W US2008003714 W US 2008003714W WO 2008115569 A1 WO2008115569 A1 WO 2008115569A1
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Prior art keywords
fas
mutein
sfas
biological fluid
conjugate
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PCT/US2008/003714
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English (en)
Inventor
Mark Douglas Howell
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Cytologic, Inc.
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Application filed by Cytologic, Inc. filed Critical Cytologic, Inc.
Publication of WO2008115569A1 publication Critical patent/WO2008115569A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K17/00—Carrier-bound or immobilised peptides; Preparation thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154

Definitions

  • This invention relates generally to the field of immunotherapy and, more specifically, to methods for inhibiting host immune responses.
  • Fas ligand (Fas-L) binding to membrane Fas receptors delivers apoptotic signals (Nagata, S., Adv. Immunol. 57:129-144 (1994)). Fas-L induced apoptosis has been shown to be an important mechanism for limiting the numbers and differentiated function of lymphocytes after the elimination of antigen (Lenardo, MJ. Immunol. Res. 27:387-398 (2003), Defrance, T. Casamayor-Palleja, M., and Krammer, P.H. Adv. Cancer Res. 86:195-225 (2002)).
  • Fas-L-induced apoptosis is mediated also by a soluble form of the membrane Fas receptor (sFas) (Cascino, L, Papoff, G., Eramo, A., and Ruberti, G. Front. Biosci. 1 :12-18 (1996)).
  • sFas binds to Fas-L and prevents the delivery of apoptotic signals through membrane Fas.
  • Elevated levels of sFas like the genetic defects described above, may disrupt Fas-L-induced apoptosis and promote the development and maintenance of autoimmune pathologies. Depletion of sFas from the circulation of patients with various autoimmune diseases may prove to be valuable in the treatment of the diseases.
  • a method for inhibiting immune responses in a mammal through the depletion of sFas present in the circulation of the mammal can be effected by removing biological fluids from the mammal and contacting these biological fluids with Fas-L muteins, capable of selectively binding to sFas.
  • Ligands useful in these methods include Fas-L muteins having specificity for soluble Fas-receptors. Moreover, mixtures of Fas-L having specificity for sFas can be used.
  • Fas-L muteins can be immobilized previously on a solid support to create an "adsorbent matrix" ( Figure 1).
  • the exposure of biological fluids to such an adsorbent matrix will permit binding by sFas, thus effecting a decrease in its abundance in the biological fluids.
  • the treated biological fluid can be returned to the patient.
  • the total volume of biological fluid to be treated and the treatment rate are parameters individualized for each patient.
  • the solid support i.e., inert medium
  • the Fas-L muteins can be mixed with the biological fluid in a "stirred reactor" ( Figure 2).
  • the Fas-L mutein-sFas complex then can be removed by mechanical or by chemical or biological means or methods, and the altered biological fluid can be returned to the patient.
  • conjugates comprising Fas-L muteins attached to a substrate.
  • Figure 1 schematically illustrates an "adsorbent matrix" configuration of an aspect of the disclosed compositions, conjugates and methods.
  • blood is removed from the patient and separated into a cellular and an acellular component, or factions thereof.
  • the acellular component, or fractions thereof is exposed to the adsorbent matrix to effect the binding and, thus, depletion of sFas.
  • the altered acellular component, or fractions thereof then is returned contemporaneously to the patient.
  • FIG. 2 schematically illustrates a "stirred reactor" configuration of an aspect of the disclosed compositions, conjugates and methods.
  • blood is removed from the patient and separated into a cellular and an acellular component, or fractions thereof.
  • Fas-L mutein is added to the acellular component, or fractions thereof.
  • the Fas-L mutein/sFas complex is removed by mechanical or by chemical or biological means or methods from the acellular component, or fractions thereof, and the altered biological fluid is returned contemporaneously to the patient.
  • Ranges may be expressed herein as from “about” one particular value, and/or to "about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • the phrase "the sample optionally may contain more than one Fas-L mutein” means that the sample may or may not contain more than one Fas-L mutein and that the description includes both a sample containing one Fas-L mutein and a sample containing more than one Fas-L mutein.
  • the disclosed methods generally are accomplished by: (a) obtaining a biological fluid from a mammal having a pathological condition; (b) contacting the biological fluid with a Fas-L mutein capable of selectively binding to sFas to produce an altered biological fluid having a reduced amount of sFas; and, thereafter (c) administering the altered biological fluid to the mammal.
  • Fas refers to soluble forms of membrane receptors for Fas.
  • the term "mammal” can be a human or a non-human animal, such as dog, cat, horse, cattle, pig, sheep, non-human primate, mouse, rat, rabbit, or other mammals, for example.
  • patient is used synonymously with the term “mammal” in describing the disclosed compositions, conjugates and methods.
  • pathological condition refers to any condition where the inhibition, by sFas, of Fas-L induced apoptosis is a component of or contributes to a disease state.
  • pathological conditions may include, but are not limited to, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and autoimmune lymphoproliferative syndrome.
  • levels of sFas are particularly suitable for the disclosed treatment.
  • Plasma levels of sFas can be determined using methods well known in the art. Those skilled in the art readily can determine pathological conditions that would benefit from the depletion of sFas according to the present methods.
  • biological fluid refers to a bodily fluid obtained from a mammal, for example, blood, including whole blood, plasma, serum, lymphatic fluid, or other types of bodily fluids. If desired, the biological fluid can be processed or fractionated, for example, to obtain an acellular component.
  • acellular biological fluid refers to the acellular component of the circulatory system including plasma, serum, lymphatic fluid, or fractions thereof.
  • the biological fluids can be removed from the mammal by any means or methods known to those skilled in the art, including, for example, conventional apheresis methods (see, Apheresis: Principles and Practice.
  • the amount of biological fluid to be extracted from a mammal at a given time will depend on a number of factors, including the age and weight of the host mammal and the volume required to achieve therapeutic benefit. As an initial guideline, one-half to four plasma volumes can be removed and, thereafter, depleted of sFas according to the present methods.
  • the term “selectively binds” means that a molecule binds to one type of target molecule, but not substantially to other types of molecules.
  • the term “specifically binds” is used interchangeably herein with “selectively binds.”
  • Fas-L mutein refers to a Fas-L variant having one or more amino acid substitutions relative to the parent sequence, encoding wild-type Fas-L, and retaining specific binding activity for Fas receptors, either soluble and/or membrane bound. Substitution of specific amino acids to create the Fas-L mutein is accomplished by methods well known in the art, for example, by altering particular codons of the nucleic acid encoding the wild-type Fas-L.
  • compositions and methods for inhibiting an immune response in a mammal advantageously uses ligands that bind to sFas to counterbalance or decrease the dampening effect of sFas on Fas-L induced apoptosis.
  • ligands also referred to herein as "Fas-L muteins”
  • Fas-L muteins can be attached to a solid support to allow the removal of sFas from a biological fluid.
  • a Fas-L mutein particularly useful in the present invention is a ligand that binds with high affinity to sFas.
  • Another useful characteristic of a Fas-L mutein is a lack of direct toxicity.
  • a Fas-L mutein lacking or having reduced Fas-L agonist activity is particularly useful.
  • a certain percentage of the bound ligand will leach from the support, for example, via chemical reactions that break down the covalent linkage or protease activity present in a biological fluid, hi such a case, the ligand will leach into the biological fluid being processed and, thus, be returned to the patient.
  • a ligand that has affinity for sFas, but has decreased ability to stimulate a biological response, that is, has decreased or low Fas-L agonist activity.
  • the ligand would still exhibit low biological activity with respect to membrane receptor signaling when reintroduced into the patient.
  • Fas-L mutein Yet another useful characteristic of a Fas-L mutein is a lack of indirect toxicity, for example, immunogenicity.
  • immunogenicity it is common for a bound ligand to leach from a matrix, resulting in the ligand being present in the processed biological fluid. When the biological fluid is returned to the patient, this results in the introduction of a low level of the ligand to the patient. If the ligand is immunogenic, an immune response against the ligand can be stimulated, resulting in undesirable immune responses, particularly in a patient in which the process is being repeated. Therefore, a ligand having low immunogenicity would minimize any undesirable immune responses against the ligand.
  • Fas-L muteins derived from the same species as the patient being treated it is particularly useful to use Fas-L muteins derived from the same species as the patient being treated.
  • a human Fas-L mutein can be used as the ligand, which is expected to have low immunogenicity given its homology to the wild type Fas-L.
  • Fas-L muteins derived from other mammalian species can be used in the respective species.
  • a Fas-L mutein can be prepared from the wild-type Fas-L of the same species as a mammal in need of treatment with, for example, the Fas-L mutein.
  • a Fas-L mutein can be prepared from the wild-type Fas-L of a species different from the species of a mammal in need of treatment with, for example, the Fas-L mutein.
  • Fas-L muteins can exhibit decreased signaling through membrane receptors, for example, decreased cytotoxic activity or in vivo toxicity, relative to the wild-type Fas-L, while retaining the ability to bind sFas.
  • a reduced signaling through membrane receptors for example, reduced cytotoxicity or in vivo toxicity, is advantageous in view of the potential leaching of the ligand from a matrix and introduction of low levels into a patient when an altered biological fluid is returned to the patient.
  • Fas-L muteins can adopt a wild- type structure. Because the muteins are highly homologous to the wild-type Fas-L sequence, these muteins can fold into a wild-type structure that retains Fas receptor binding activity. Such a wild-type structure means that the same amino acid residues are exposed on the surface of the molecule as in the wild-type Fas-L, except for possibly the mutant amino acid residue. Such a wild-type folding means that the Fas-L muteins will have little or no immunogenicity in the respective mammalian species.
  • Fas-L muteins additional to the specific muteins exemplified herein can be used in the disclosed compositions and methods.
  • Fas-L muteins suitable for use in the disclosed compositions, conjugates and methods.
  • Fas-L muteins having relatively high affinity for Fas receptors and decreased signaling through membrane receptors, for example, decreased cytotoxicity or in vivo toxicity, relative to wild-type Fas-L are particularly useful in the disclosed compositions, conjugates and methods.
  • One skilled in the art can readily determine additional suitable Fas-L muteins based on methods well known to those skilled in the art.
  • Fas-L muteins as disclosed herein.
  • a particularly useful Fas-L mutein has about 2-fold, about 3-fold, about 4-fold, about 5- fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 11- fold, about 12-fold, about 13-fold, about 14-fold, about 15-fold, about 16-fold, about 17-fold, about 18-fold, about 19-fold, about 20-fold, about 25-fold, about 30-fold, or even higher fold reduced binding affinity for Fas-L receptors, particularly membrane bound Fas-L receptors, relative to the wild-type/wild type Fas-L.
  • Fas-L mutein has about 5-fold, about 10-fold, about 50-fold, about 100-fold, about 150-fold, about 200-fold, about 300-fold, about 500-fold, about 1000- fold, about 2000-fold, about 3000-fold, about 4000-fold, about 5000-fold, about 6000- fold, about 7000-fold, about 8000-fold, about 9000-fold, about 10,000-fold, about 20,000-fold, about 30,000-fold, about 50,000-fold, or even higher fold reduced signaling through the membrane receptors, for example, reduced cytoxicity or in vivo toxicity, relative to the wild type Fas-L. It is understood that a Fas-L mutein can have reduced binding affinity and/or reduced cytoxicity, as discussed above and disclosed herein.
  • conjugate comprising a Fas-L mutein attached to a substrate.
  • the method can include the steps of obtaining a biological fluid from the mammal; contacting the biological fluid with a Fas-L mutein having specific binding activity for sFas; removing the Fas-L mutein bound to the sFas from the biological fluid to produce an altered biological fluid having a reduced amount of sFas; and administering the altered biological fluid to the mammal.
  • the biological fluid can be, for example, blood, plasma, serum or lymphatic fluid, including whole blood.
  • a method using whole blood as the biological fluid can further include the step of separating the whole blood into a cellular component and an acellular component or a fraction of the acellular component, wherein the acellular or the fraction of the acellular component contains sFas.
  • the method can additionally include the step of combining the cellular component with the altered acellular component or altered fraction of the acellular component to produce altered whole blood, which can be administered to the mammal as the altered biological fluid. Accordingly, the cellular component and the altered acellular component or altered fraction of the acellular component can be administered separately to the mammal.
  • the Fas-L mutein can be attached to a carrier.
  • carriers include, but are not limited to, proteins, complex carbohydrates, and synthetic polymers such as polyethylene glycol.
  • Fas-L muteins useful with the disclosed compositions, conjugates and methods are well known to those skilled in the art. Such methods include, for example, recombinant DNA and synthetic techniques, or a combination thereof. Fas-L muteins can be expressed in prokaryotic or eukaroytic cells, for example, mammalian, insect, yeast, and the like. If desired, codons can be changed to reflect any codon bias in a host species used for expression.
  • a Fas-L mutein can be attached to an inert medium to form an adsorbent matrix ( Figure 1).
  • the Fas-L mutein can be, for example, covalently attached to a substrate such as an inert medium to form a conjugate, wherein the Fas-L mutein is immobilized.
  • the term "inert medium" is intended to include solid supports to which the Fas-L mutein(s) can be attached.
  • Particularly useful supports are materials that are used for such purposes including, but not limited to, for example, cellulose-based hollow fibers, synthetic hollow fibers, silica-based particles, flat or pleated membranes, macroporous beads, agarose-based particles, and the like.
  • the inert medium can be in the form of a bead, for example, a macroporous bead or a non- porous bead.
  • exemplary macroporous beads include, but are not limited to, naturally occurring materials such as agarose, cellulose, controlled pore glass, or synthetic materials such as polyacrylamide, crosslinked agarose (such as Trisacryl , Sephacryl,
  • a macroporous bead comprises Actigel .
  • Exemplary non- porous beads include, but are not limited to, silica, polystyrene, latex, and the like.
  • Hollow fibers and membranes can also be composed of natural or synthetic materials.
  • Exemplary natural materials include, but are not limited to, cellulose and modified cellulose, for example, cellulose diacetate or triacetate.
  • Exemplary synthetic materials include, but are not limited to, polysulfone, polyvinyl, polyacetate, and the like.
  • the Fas-L mutein can be attached to the inert medium by any means or methods known to those skilled in the art including, for example, covalent conjugation.
  • the Fas-L mutein can be associated with the inert matrix through high-affinity, non-covalent interaction with an additional molecule which has been covalently attached to the inert medium.
  • a biotinylated Fas-L mutein can interact with avidin or streptavidin previously conjugated to the inert medium.
  • the adsorbent matrix thus produced can be contacted with a biological fluid, or a fraction thereof, through the use of an extracorporeal circuit.
  • extracorporal, adsorbent matrices has been extensively reviewed (see Kessler, Blood Purification 11 :150-157 (1993)).
  • the biological fluid can be exposed to a Fas-L mutein in a mixing chamber and, thereafter, the Fas-L mutein/sFas complex can be removed by means or methods known to those skilled in the art, including, for example, by mechanical or by chemical or biological separation methods.
  • a mechanical separation method can be used in cases where the Fas-L mutein, and therefore the Fas-L mutein/sFas complex, represent the largest components of the treated biological fluid.
  • filtration can be used to retain the Fas-L mutein and sFas associated therewith, while allowing all other components of the biological fluid to permeate through the filter and, thus, to be returned to the patient.
  • the Fas-L mutein and sFas associated therewith can be removed from the treated biological fluid through exposure to an adsorbent matrix capable of specifically attaching to the Fas-L mutein.
  • an adsorbent matrix capable of specifically attaching to the Fas-L mutein.
  • a matrix constructed with antibodies reactive with a Fas-L mutein can serve this purpose.
  • Fas-L mutein/sFas complex such as Fas-L mutein bound to sFas
  • removal of the Fas-L mutein/sFas complex, such as Fas-L mutein bound to sFas from a biological fluid can be accomplished by separating the biological fluid and the Fas-L mutein/sFas complex in any suitable manner. Either or both the Fas-L mutein/sFas complex and the
  • Fas-L mutein bound to sFas from a biological fluid can be passively or actively separated from the other.
  • removal of Fas-L mutein bound to sFas from a biological fluid can be accomplished by, for example, actively removing Fas-L mutein bound to sFas from the biological fluid or actively removing the biological fluid from the Fas-L mutein bound to sFas.
  • the treated or altered biological fluid having a reduced amount of sFas, can be returned to the patient receiving treatment along with untreated fractions of the biological fluid, if any such fractions were produced during the treatment.
  • the altered biological fluid can be administered to the mammal by any means or methods known to those skilled in the art, including, for example, by infusion directly into the circulatory system.
  • the altered biological fluid can be administered immediately after contact with the Fas-L mutein in a contemporaneous, extracorporeal circuit, hi this circuit, the biological fluid can be (a) collected, (b) separated into cellular and acellular components, if desired, (c) exposed to the Fas-L mutein, and if needed, separated from the Fas-L mutein bound to sFas, (d) combined with the cellular component, if needed, and (e) readministered to the patient as altered biological fluid, hi a further aspect, the altered acellular biological fluid can be administered to the patient at an infusion site different from the site where the cellular component of the biological fluid is administered to the patient.
  • the administration of the altered acellular biological fluid to the patient can be simultaneous with, precede, or follow the administration of the cellular component of the biological fluid to the patient. Alternatively, the administration of the altered biological fluid can be delayed under appropriate storage conditions readily determined by those skilled in the art.
  • the entire process can be repeated.
  • Those skilled in the art can readily determine the benefits of repeated treatment by monitoring the clinical status of the patient, and correlating that status with the concentration(s) of sFas in circulation prior to, during, and after treatment.
  • the apparatus can be composed of: (a) a means for separating the biological fluid into a cellular component and an acellular component or fraction thereof; (b) an adsorbent matrix having attached thereto a Fas-L mutein or a stirred reactor as described above to produce an altered acellular component or fraction thereof; and (c) a means for combining the cellular fraction with the altered acellular component or fraction thereof.
  • the apparatus is particularly useful for whole blood as the biological fluid in which the cellular component is separated either from whole plasma or a fraction thereof.
  • sFas useful in perfecting and practicing the invention can be produced recombinantly either in E. coli or other bacterial genera, or in eukaryotic cell culture essentially as described (see U.S. Patent No. 6,379,708, which is incorporated herein by reference).
  • the construction of expression plasmids, the methods for transforming and selecting cultured cells, for purifying the sFas, and associated assay methods are well known in the art.
  • EXAMPLE 2 Production, Purification, and Characterization of Fas-L muteins
  • Fas-L muteins also can be produced recombinantly either in E. coli or other bacterial genera, or in eukaryotic cell culture essentially as described (see U.S. Patent Application No. 11/234,057, which is incorporated herein by reference).
  • the construction of expression plasmids, the methods for transforming and selecting cultured cells, for purifying the Fas-L muteins, and associated assay methods are well known in the art.
  • Fas-L muteins produced as described above, can be immobilized on a solid support to create adsorbent matrices.
  • purified Fas-L muteins can be covalently conjugated to macroporous beads such as cyanogen bromide (CNBr)
  • Sepharose 4B Sepharose 4B, Actigel ALD, and others, according to the manufacturer's instructions.
  • the resulting matrices can be packed in individual column housings and washed extensively with phosphate buffered saline prior to use.
  • sFas from normal human plasma using a Fas-L mutein adsorbent matrix initially can be evaluated in vitro.
  • plasma may be spiked with known concentrations of purified sFas, passed through the adsorbent matrix, and the effluent collected.
  • Capture ELISA can be used to quantify the levels of the sFas in the pre- and post-matrix plasma samples. The efficiency of sFas depletion, thus, can be calculated.
  • Fas-L mutein adsorbent device to deplete sFas from plasma, when used in an extracorporeal circuit not unlike that employed for therapeutic plasma exchange, is readily evaluated. Briefly, blood is removed from a mammal and delivered to a Cobe Spectra, a centrifugal plasma separator, using a Cobe Spectra Therapeutic Plasma Exchange disposable tubing set. Once separated, the blood cells and plasma are routed, independent of each other, through the remainder of the system. The plasma component is passed through the Fas-L mutein adsorbent device as illustrated in Figure 1 herein. The treated plasma is recombined with the blood cells and returned through the catheter to the mammal. One-half to four plasma volumes can be treated during a single session, and the treatment may be repeated.
  • Plasma samples can be obtained from the extracorporeal circuit immediately prior to entering the adsorbent device and immediately after exiting the adsorbent device.
  • the levels of sFas in these plasma samples can be determined using capture ELISA and the efficiency of depletion can be calculated.

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Abstract

L'invention concerne un procédé pour inhiber une réponse immunitaire chez un mammifère pour faciliter l'élimination de diverses maladies chroniques. Le procédé implique l'élimination de sFas de la circulation du mammifère, permettant ainsi une signalisation plus efficace par Fas-L à travers la membrane Fas. L'élimination de sFas est accomplie en mettant en contact des liquides biologiques d'un mammifère avec une ou plusieurs mutéines Fas-L capables de se lier à, et ainsi d'appauvrir, sFas provenant des liquides biologiques. Est particulièrement utile une matrice absorbante composée d'un substrat biocompatible inerte lié de manière covalente à une mutéine Fas-L, capable de se lier spécifiquement à sFas.
PCT/US2008/003714 2007-03-21 2008-03-20 Procédé pour inhiber les réponses immunitaires chez les mammifères utilisant des mutéines de ligand fas WO2008115569A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020206A1 (fr) * 1994-12-23 1996-07-04 Uab Research Foundation Antigene du fas secrete par l'homme
US6379708B1 (en) * 1999-11-20 2002-04-30 Cytologic, Llc Method for enhancing immune responses in mammals
US20040126859A1 (en) * 1996-11-13 2004-07-01 Keting Chu Mutant forms of Fas ligand and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996020206A1 (fr) * 1994-12-23 1996-07-04 Uab Research Foundation Antigene du fas secrete par l'homme
US20040126859A1 (en) * 1996-11-13 2004-07-01 Keting Chu Mutant forms of Fas ligand and uses thereof
US6379708B1 (en) * 1999-11-20 2002-04-30 Cytologic, Llc Method for enhancing immune responses in mammals

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