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WO1991011174A1 - Procede de prevention de la suppression des defenses immunitaires chez des patients souffrant de traumatismes - Google Patents

Procede de prevention de la suppression des defenses immunitaires chez des patients souffrant de traumatismes Download PDF

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Publication number
WO1991011174A1
WO1991011174A1 PCT/US1991/000506 US9100506W WO9111174A1 WO 1991011174 A1 WO1991011174 A1 WO 1991011174A1 US 9100506 W US9100506 W US 9100506W WO 9111174 A1 WO9111174 A1 WO 9111174A1
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WIPO (PCT)
Prior art keywords
response modifier
biological response
brm
ribosomes
cti
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Application number
PCT/US1991/000506
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English (en)
Inventor
Catherine Anne Mccall
Verlyn Monroe Peterson
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University of Colorado Foundation Inc
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University of Colorado Foundation Inc
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Publication date
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Publication of WO1991011174A1 publication Critical patent/WO1991011174A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/05—Immunological preparations stimulating the reticulo-endothelial system, e.g. against cancer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to the treatment of patients suffering from severe trauma, such as burns. More particularly, the invention relates to the use of a non-specific biological response modifier for improving the ability of traumatized patients to resist opportunistic infections.
  • T helper/suppressor ratio is altered in favor of the T suppressor (9) and production of IL-2 is lowered (10) in trauma patients.
  • Natural killer cells (NK) which are an important line of defense against virus infection (11) , are not functional in trauma patients, as measured by their ability to kill virally infected target cells (12) , although their numbers appear normal (13) .
  • the numbers of these cells are depleted after severe injury, and examination of bone marrow reveals a lowering in the numbers of stem cells (granulocyte-macrophage colony forming units, GM-CFU) (14) and the presence of humoral factor(s) which inhibit stem cell proliferation.
  • stem cells granulocyte-macrophage colony forming units, GM-CFU
  • cytokines such as interleukin-2 sets off an as yet ill-defined cascade of other cytokines which can lead to unexpected effects including considerable toxicity.
  • the proliferation, maturation and function of hematopoietic cells is under the control of a complex series of interacting mediators (15) .
  • Phase l clinical trials of GM-CSF have shown that significant elevations of granulocyte counts can be achieved in cytopenic patients with little toxicity
  • the cells induced during GM-CSF infusion are functionally defective in at least one respect - the ability to migrate from the blood into tissues (17) .
  • GM-CSF infusion will induce cells capable of dealing with sepsis, infections in tissues such as lung may remain untouched.
  • the quantities of GM-CSF required for optimal stimulation of myelopoiesis appear to cause an inappropriate timing of expression of vascular adhesion molecules on granulocytes.
  • the optimal use of recombinant cytokines will almost certainly require combination therapy consisting of the timed administration of multiple factors in a sequence designed to mimic normal hematopoiesis.
  • BRM biologic response modifier
  • Figures 1 through 8 illustrate various parameters, as noted on the titles, measured in connection with an experiment using a mouse model.
  • AGC Absolute granulocyte count
  • AMC Absolute monocyte count
  • ALC Absolute lymphocyte count
  • BM Bone marrow
  • CFU-GM Colony forming units - granulocyte macrophage
  • SPL Spleen
  • the invention comprises a method of treating a patient having trauma- induced immune suppression in order to enhance the ability of the patient's immune system to resist opportunistic infection.
  • a therapeutically effective amount of a non-specific biological response modifier is administered to the patient.
  • the biological response modifier comprises natural membrane vesicles and ribosomes, in a suspending buffer.
  • the ribosomes and vesicles are both derived from the bacterium Serratia marcescens .
  • the invention comprises use of a non-specific biological response modifier in the manufacture of a medicament for the treatment of trauma- induced immune suppression.
  • the non-specific biological response modifier will be comprised of natural membrane vesicles and ribosomes in a suspending buffer.
  • the ribosomes and vesicles will both be derived from the bacterium Serratia marcescens .
  • Non-toxic means within a level of toxicity which is tolerable by the mammalian host receiving biologic response modifier therapy.
  • Non-immunogenic means evoking a sufficiently low immunogenic response, or no response at all, such that undesired, chronic inflammatory and hypersensitivity responses are not elicited, significantly, in the mammalian host.
  • Mean diameter means the mean diameter of MSD Particle Size Distribution Analysis as measured on a BI- 90 (Brookhaven Instrument Corp.) particle sizer. The measurement involves an intensity weighting of the size averaging process and is explained more fully in the Operator's Manual for the instrument, Chapter 6, incorporated herein by reference.
  • Substantially non-pathogenic in humans means not or rarely associated with disease in humans of normal health. Since most microorganisms are capable of causing opportunistic infections under the right circumstances, such as in persons whose immune system has been compromised, this definition excludes only those organism which typically cause non-opportunistic infections.
  • “Tolerable level of endotoxin, cell walls, and cell membrane fragments” means that any such fraction, if present, have low enough level of biologic activity to maintain a non-toxic characteristic as defined herein.
  • Immunune suppressing response means an immune response which so attenuates the effect of the desired immune response as to be unacceptable for medical purposes.
  • Natural membrane vesicles means membrane vesicles prepared from membranes which are derived from living or dead nature cells.
  • CTI-BRM shall mean the biological response modifier described in the foregoing application.
  • CTI-BRM is, at the time of filing this application, undergoing Phase II Clinical Trials for cancer pursuant to regulations of the Food and Drug Administration of the United States of America.
  • CTI-BRM comprises natural membrane vesicles and ribosomes in a suspending buffer.
  • the vesicles are comprised of cellular membrane material and are endogenous to a selected organism.
  • the ribosomes are also endogenous to the selected organism.
  • the biologic response modifier is substantially free of intact cells, cell walls, and cell membrane fragments.
  • the selected organism is one which does not evoke an immune suppressing response, is non-pathogenic in humans, and is one from which membrane vesicles are capable of being formed from cell membrane material and which vesicles are readily endocytosed by the monocyte macrophage cell line.
  • CTI-BRM exhibits a mean diameter of at least about 180nm on particle size analysis.
  • CTI-BRM Further description of the CTI-BRM is provided in the aforementioned United States Patent and published PCT application. Such description, and the method of preparation, are set forth with particularity in that application and are incorporated herein by reference. The ability of CTI-BRM to alter the levels of various white blood count and neutrophil levels in cancer patients is described in the aforementioned United States Patent and published PCT application.
  • Dosage regimens described in the aforementioned United States Patent and published PCT patent application included dosage levels ranging from 0.25 to 10 milligrams administered from 3 to 6 times spaced at 7 day intervals and administered subcutaneously. Toxicity trials indicated no significant toxicity problems with those dosage regimens and further indicated that the product was well tolerated by the human patients. Adjuvant arthritis, granulo as, ulcerations, and similar effects of toxic components are minimized or eliminated by the use of the CTI-BRM.
  • a preferred source of the material for the CTI-BRM is the organism Serratia marcescens .
  • Serratia marcescens is a well known organism and many strains are publicly available from a number of sources. For example, some sixty strains are available from the Budapest Treaty approved depository, American Type Culture Collection, Rockville, Maryland, 20852, U.S.A.
  • other organisms are suitable as source for the membrane vesicles and ribosomes utilized in the CTI-BRM.
  • Such microorganisms should be not a member of the microflora of the patient.
  • the microorganisms common bacterial antigen must not react or at least must be poorly cross-reactive with organisms making up the normal microflora of the patient.
  • suitable microorganism sources other than Serratia marcescens are Erwinia chrysanthemi (pectobacterium) and Enterobacter aerogenes .
  • bacterial cells of a strain of microorganism which is not present in the microflora of the patient to be treated and which has a common bacterial antigen which does not cross react or is poorly cross reactive with organisms making up the normal microflora of the patient to be treated are cultivated.
  • the cultivated cells are harvested and cell membrane is disassociated with an appropriate detergent.
  • the cellular concentrate is subjected to disruption mechanically at a pressure in excess of 10,000 psi to produce membrane vesicles with a mean diameter not less than 180 nm.
  • the membrane vesicles and free ribosomes are separated from the remaining cellular material in the cellular lysate.
  • CTI-BRM is a powerful immunomodulator: it is rapidly phagocytosed by monocytes/macrophages which then show increased phagocytic, bactericidal and tumoricidal activity (21) .
  • Patients injected subcutaneously with CTI-BRM show significant rises in granulocyte counts 24 hours later (22) .
  • Co-culture of CTI BRM with human peripheral blood mononuclear cells results in elevation of NK activity (23) , increased T-cell mediated cytotoxicity, and augmented lymphocyte and monocyte antibody mediated cytotoxicity (ADCC) (24) .
  • ADCC lymphocyte and monocyte antibody mediated cytotoxicity
  • CTI-BRM This ability of CTI-BRM to stimulate endogenous production of cytokines, inducing proliferation, maturation or enhancement of function of macrophages and lymphocytes, makes it useful for the treatment of post-trauma immunosuppression.
  • Normal mice injected with CTI-BRM via intravenous, intraperitoneal, and subcutaneous routes show an increase in the number of leukocytes in the blood, spleen and peritoneal cavity. Mice suffering a 20% full thickness burn can also respond to CTI-BRM by elevating their blood and splenic leukocyte counts: the majority of these cells are granulocytes and monocytes.
  • Pretreatment of mice given a lethal dose (LD 70-90) of Lister ia results in significant improvement in survival.
  • CTI-BRM CTI-BRM restore the immune systems of traumatized mammals was demonstrated in connection with a mouse model traumatized by burn injuries.
  • the mouse model employed is a well-known one for which results may be readily extrapolated to humans by those skilled in the art.
  • the methods employed were as follows:
  • mice Female CF1 mice are dorsally shaved and depilitated with a depilatory cream: 24 hours later the mice are deeply anesthetized with methoxyfluorothane gas, secured in a template and the shaved dorsum exposed to steam for 7 seconds: this results in a 20% full thickness burn. Immediately postburn, mice are give 1 ml sterile normal saline i.p to counteract shock. In this model, a significant fall in leukocyte count is usually measurable 3 days after burn, and maximal immunosuppression, as measured by the DNCB sensitization assay, occurs 14 days post burn (26) .
  • mice are killed by C0 2 suffocation, the abdomen swabbed with alcohol and overlying abdominal skin cut and pinned back to allow access to the body wall. An incision is made in the body wall and the spleen is removed with sterile forceps.
  • Differentials are performed on standard smear preparations of blood, and on cytocentrif ge preparations of spleen cells, stained with Wright-Geimsa stain (Diff-Quik, Sigma) .
  • the mean CFU-GM for each cell preparation is calculated and the number of CFU per tibia or spleen determined by multiplying the number of CFU/plate by the quotient of the number of nucleated cells/organ divided by the number of nucleated cells cultured per plate.
  • DNFB dissolved in 4:1 acetone/olive oil is painted onto the shaved abdomen. Five days later, the ear thickness is each mouse is measured with a caliper and each ear then immediately painted with 20 / zl of
  • mice receiving CTI-BRM were burned mice receiving CTI-BRM, and burned mice receiving NaCl (buffer) .
  • FIG. 1 shows the mean white count for each experimental group at days 3, 10, and 17 postburn.
  • Figure 1 shows the mean white count for normal mice whose value was 1.92 X 10 6 , is indicated by the point NL at the far left.
  • the burned mice receiving CTI-BRM had a significantly higher average white count than burned mice receiving buffer.
  • FIG 2 the absolute granulocyte count is illustrated. Burned mice receiving CTI-BRM had marked elevations in absolute granulocyte count compared to burned animals receiving buffer. Again, the point NL at the left indicates a value for normal, untreated mice.
  • Total bone marrow cellularity in the tibia of the experimental mice is shown in Figure 5. Again, the normal tibial cellularity is 6.1 x 10 6 and is shown by the bar on the left. At day 3, CTI-BRM had no significant effect on total bone marrow cellularity. CTI-BRM appeared to have no significant effect on bone marrow cellularity.
  • Figure 6 shows the number of granulocyte macrophage stem cells present in the tibial bone marrow of mice in the experimental groups.
  • CTI-BRM caused a slight increase in CFU-GM tibia at day 3 compared to buffer treated burned mice.
  • stem cell numbers fell dramatically in burned mice receiving CTI-BRM or buffer at days 10 and 17. The significance of this awaits further investigation.
  • the number of stem cells was approximately equal in both CTI-BRM and buffer-treated burned mice.
  • Figure 8 describes the number of granulocyte macrophage stem cells found in spleens of mice in the study. CTI-BRM appeared to significantly increase the number of splenic stem cells at days 10 and 17 in the burned mice.
  • Bone marrow cellularity seems to decrease slightly burned mice, and bone marrow stem cells also appear to decrease in number.
  • mice were burned at day 0 and given a single injection of CTI-BRM at day 9. Abdomens were painted at days 14 and 15 and ear swelling was determined at days 19 and 20. Burn injury again resulted in significant immunosuppression.
  • CTI-BRM had no significant effect on T-cell mediated immunity when looking at the effects of CTI-BRM compared to non-treated controls. A slight increase in ear swelling in the normal mice receiving buffer was modest and not statistically significant. In summary, no advantage appears to be derived from the administration of a single vs. double dose of CTI-BRM.
  • Administration of the CTI-BRM pursuant to the method of the invention is capable of restoring the immune system in the case of patients suffering from severe trauma.
  • the method of the invention is safe in that it is well tolerated by patients. Restoration of the immune system in such patients restores their ability to withstand opportunistic infection, thereby greatly enhancing their chances for recovery.
  • the present invention provides a method of treating a patient having trauma-induced immune suppression in order to enhance the ability of the patient's immune system to resist opportunistic infection.
  • a therapeutically effective amount of a non-specific biological response modifier is administered to the patient.
  • the biological response modifier comprises natural membrane vesicles and ribosomes, in a suspending buffer.
  • the ribosomes and vesicles are both derived from the bacterium Serratia marcescens .
  • the present invention also teaches use of a non-specific biological response modifier in the manufacture of a medicament for the treatment of trauma-induced immune suppression.
  • the non-specific biological response modifier will be comprised of natural membrane vesicles and ribosomes in a suspending buffer.
  • the ribosomes and vesicles will both be derived from the bacterium Serratia marcescens .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Veterinary Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Procédé de traitement d'un patient présentant une suppression des défenses immunitaires induite par un traumatisme, permettant d'améliorer la capacité du système immunitaire des patients de résister aux infections à germes opportunistes. Selon le procédé, on administre au patient une dose thérapeutiquement efficace d'un modificateur de réponse biologique nonspécifique. Le modificateur de réponse comprend, de préférence, des vésicules à membranes naturelles et des ribosomes, dans un tampon de suspension. A la fois les ribosomes et les vésicules sont, de préférence, dérivés de la bactérie Serratia marcescens. Le modificateur de réponse biologique est caractérisé par l'absence de toxicité ainsi que par une cohérence du produit, évitant ainsi les problèmes rencontrés avec d'autres immunomodulateurs. De plus, l'invention comprend l'utilisation d'un modificateur de réponse biologique non spécifique dans la fabrication d'un médicament destiné au traitement de la suppression des défenses immunitaires induite par un traumatisme. Le modificateur de réponse biologique non spécifique est, de préférence, composé de vésicules à membrane naturelle et de ribosome dans un tampon à suspension. A la fois les ribosomes et les vésicules sont, de préférence, dérivés de la bactérie Serratia marcescens.
PCT/US1991/000506 1990-01-25 1991-01-24 Procede de prevention de la suppression des defenses immunitaires chez des patients souffrant de traumatismes Ceased WO1991011174A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US46996890A 1990-01-25 1990-01-25
US469,968 1990-01-25

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997005899A3 (fr) * 1995-08-04 1997-05-29 Univ Guelph Nouveaux vaccins et nouvelles compositions pharmaceutiques utilisant des vesicules de membrane de micro-organismes et leurs procedes d'elaboration
AU703924B2 (en) * 1994-07-16 1999-04-01 Meda Pharma Gmbh & Co. Kg Formulation for administration by inhalation
JP3192976B2 (ja) 1995-09-28 2001-07-30 ロレアル リボソームフラクションおよびこれを含有する組成物
US6916478B2 (en) 1995-08-04 2005-07-12 University Of Guelph Vaccines and pharmaceutical compositions using membrane vesicles of microorganisms, and methods for preparing same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4663161A (en) * 1985-04-22 1987-05-05 Mannino Raphael J Liposome methods and compositions
US4826687A (en) * 1985-06-06 1989-05-02 National Institute Of Health Influenza vaccine
US4871488A (en) * 1985-04-22 1989-10-03 Albany Medical College Of Union University Reconstituting viral glycoproteins into large phospholipid vesicles
US4971801A (en) * 1986-06-09 1990-11-20 Cell Technology, Inc. Biologic response modifier

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4663161A (en) * 1985-04-22 1987-05-05 Mannino Raphael J Liposome methods and compositions
US4871488A (en) * 1985-04-22 1989-10-03 Albany Medical College Of Union University Reconstituting viral glycoproteins into large phospholipid vesicles
US4826687A (en) * 1985-06-06 1989-05-02 National Institute Of Health Influenza vaccine
US4971801A (en) * 1986-06-09 1990-11-20 Cell Technology, Inc. Biologic response modifier

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU703924B2 (en) * 1994-07-16 1999-04-01 Meda Pharma Gmbh & Co. Kg Formulation for administration by inhalation
WO1997005899A3 (fr) * 1995-08-04 1997-05-29 Univ Guelph Nouveaux vaccins et nouvelles compositions pharmaceutiques utilisant des vesicules de membrane de micro-organismes et leurs procedes d'elaboration
US6916478B2 (en) 1995-08-04 2005-07-12 University Of Guelph Vaccines and pharmaceutical compositions using membrane vesicles of microorganisms, and methods for preparing same
JP3192976B2 (ja) 1995-09-28 2001-07-30 ロレアル リボソームフラクションおよびこれを含有する組成物

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Publication number Publication date
AU7239191A (en) 1991-08-21

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