EP0331716A4 - Procede de modulation selective de l'expression et de la fonction d'un determinant de surface cellulaire, et production de nouvelles cellules humaines ainsi produites. - Google Patents

Procede de modulation selective de l'expression et de la fonction d'un determinant de surface cellulaire, et production de nouvelles cellules humaines ainsi produites.

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Publication number
EP0331716A4
EP0331716A4 EP19880908632 EP88908632A EP0331716A4 EP 0331716 A4 EP0331716 A4 EP 0331716A4 EP 19880908632 EP19880908632 EP 19880908632 EP 88908632 A EP88908632 A EP 88908632A EP 0331716 A4 EP0331716 A4 EP 0331716A4
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EP
European Patent Office
Prior art keywords
cell
cells
human cells
human
surface determinants
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP19880908632
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German (de)
English (en)
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EP0331716A1 (fr
Inventor
Arthur Allen Vandenbark
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Individual
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Individual
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Publication of EP0331716A1 publication Critical patent/EP0331716A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • This invention generally relates to a process in which the expression and function of a human cell- surface determinant on human cells is selectively modulated and to the novel selectively modulated human cells produced by that process.
  • selectively modulating the expression and function of specific human cell-surface determinants certain human cells can in turn be protected from debilitants and thereby can be maintained intact and available to function.
  • the human immune system when functional, acts to protect the body against infectious agents, including viruses, bacteria, parasites, and the like.
  • An individual's ability to combat these agents, or other substances (antigens) recognized as foreign by ' the body's immune system, is critical to health and survival. Under normal circumstances, the immune system is able to contain most infections, thus allowing complete recovery. When the immune system is inadequate, however, severe infections may result.
  • lymphocytes Two classes of white blood cells, macrophages and lymphocytes, are primarily responsible for immunity. Macrophages digest and destroy infectious agents, and then present structural information about these agents to the lymphocytes. Lymphocytes are divided into two general categories. One class of lymphocytes, B cells, produce antibodies in response to infectious agents. Antibodies have unique combining sites that recognize the distinguishing structural features of individual antigens. When antibody molecules bind to antigen, the interaction sets in motion a chain of events which may neutralize the effects of the foreign substance. The other group of lymphocytes, T cells, produce unique membrane receptors- which recognize the individual antigen structures presented by the macrophage. When T cells interact with antigen, a variety of hormones (lymphokines) are released which may induce inflammation, amplify or suppress antibody formation by B cells, or destroy directly foreign cells such as tumors or transplanted organs.
  • lymphokines hormones
  • lymphokines and monokines are controlled, to a large extent, by lymphokines and monokines (macrophage hormones). There are many different lymphokines and monokines, each of which has distinctive chemical and functional properties.
  • Gangliosides are a diverse group of glycosphingolipids characterized by the presence of one or more sialic acid units on the oligosaccharide chain. Gangliosides have been found to inhibit T cell proliferation and function. This has been suggested in the following . articles: Lengle, E.E., et al., "Inhibition of Lectin-Induced Mitogenic Response of Thymocytes By Glycolipids," in Cancer Research, Vol. 39, p. 817 (1979), and Whisler, R.L., et al., "Regulation of Lymphocyte Responses by Human Gangliosides: Characteristics of Inhibitory Effects and the Induction of Impaired Activation," in the Journal of Immunology, Vol.
  • gangliosides inhibit the encephalitogeni ⁇ activity and effect the expression of the T-helper cell phenotype. Gangliosides were found to inhibit the fluorescent staining of the W3/25 monoclonal antibody on BP-1 rat T-helper cell line in vitro. This inhibitory effect was not exhibited by cells stained with W3/13 (T-total), OX-8 (T-non-helper) or OX-6(Ia) antibodies. 'See Offner, H. and A.A. Vandenbark, "Gangliosides Inhibit Phenotypic and
  • U.S. 4,476,119; U.S. 4,593,091 and U.S. 4,639,437 relate to methods for preparing ganglioside inner ester derivatives, the use thereof in pharmaceutical compositions, as well as providing inhalation kits containing such ganglioside derivatives, for promoting nerve regeneration by stimulating nerve sprouting.
  • An extremely important property of a biologically active material in humans is its ability to discriminate, i.e., to modulate selectively the expression and function of a given cell-surface determinant.
  • Antibodies are discriminatory agents which selectively bind to specific cell-surface determinants on particular human cells.
  • the functional effects on a given cell of this discriminatory, selective binding are unpredictable and must be determined through experimentation on an ad hoc basis.
  • Chemical compositions such as drugs and the like, on the other han ⁇ * d, are non-discrim ⁇ inatory and may affect many types of hutan cellis.
  • a chemical composition such as methyltrexate* a chemotherapeutic agent for treatment of cancer, functions by inhibiting the proliferation of all actively dividing human cells.
  • This chemical is non- selective and, therefore, does not discriminate between the destruction of malignant and non-malignant cells.
  • many necessary human functions involving rapidly dividing cells e.g., the immune system
  • This invention is directed to a process for inhibiting infection in humans by selectively modulating the expression of a specific cell-surface determinant, namely, the CD4 molecule on human cells, with a chemical agent.
  • the CD4 (T4) antigen of the helper T-lymphocyte is thought to be an essential component of the receptor for the AIDS retrovirus. See Dalgleish, A.G., et al., "The CD4 (T4) Antigen of the Receptor For the AIDS Retrovirus," Nature, Vol. 312, p. 763 (1984).
  • the chemical agent is a ganglioside composition which induces the rapid and selective disappearance of CD4 cell-surface determinants from human cells.
  • Human cells after treatment with this ganglioside composition no longer express the cell-surface CD4 molecules, and are thus selectively inhibited from receptivity (infection) by viruses, including the human immunodeficiency virus ("HIV”) which causes acquired immunodeficiency syndrome, commonly know as AIDS, or other viruses such as retroviruses, which infect target cells through the CD4 cell-surface molecules.
  • HIV human immunodeficiency virus
  • Immune T lymphocytes and macrophages play an essential rule in protecting against infectious diseases. Certain viruses, such as HIV, selectively attack both of these cell types which possess the CD4 molecule on the cell surface. When these T lymphocytes and macrophages are attacked and destroyed after infection with HIV, global immunodeficiency results, leading to severe complications and death due to secondary infections. Thus, prevention of HIV infections by gangliosides and the maintenance of effective T lymphocyte responses have widespread prophylactic and therapeutic potential in AIDS. Attempts have been made by researchers to overcome the AIDS health hazard by inhibiting HIV prior to its interaction with the CD4 cell-surface determinant. Moreover, other scientists have tried to solve the problem by blocking the CD4 reception mechanism so that HIV will not combine therewith. To date, these undertakings have been unproductive and the epidemic continues unchecked.
  • ganglioside shall be defined as any compound including a lipid (ceramide), or a chemically-modified lipid, and a sialated oligosaccharide, or a chemically- modified sialated ogliosaccharide, respectively.
  • the ganglioside compositions employed in producing the CD4- modulated human cells are preferably selected from a group consisting of mono-sialated gangliosides, di- sialated gangliosides, tri-sialated gangliosides, tetra-sialated gangliosides, modified gangliosides, and mixtures thereof.
  • Selective modulation of the human cells is preferably conducted in an environment of substantially low blood serum concentration in order to avoid the neutralizing effects of serum on the ganglioside composition.
  • an effective concentration of the ganglioside composition is added to overcome such serum neutralization.
  • the selectivity of modulation of the CD4 cell- surface determinants is carried out without effecting the expression and function of other cell-surface determinants. In this way, one can inhibit the receptivity the CD4 cell-surface determinants to viruses without endangering the desired effective functioning of any other determinants.
  • the selective modulation of this invention can be maintained by providing effective amounts of said ganglioside composition at a level sufficient to prevent re-expression of said CD4 cell-surface determinants on the human cells.
  • a user can continue the ganglioside addition step as long as they deem it necessary.
  • the addition of said ganglioside composition can be terminated thereby allowing the re-expression of said CD4 cell-surface determinants on said human cells.
  • This allows the user to re-express the receptive attributes of the CD4 molecule when needed and to modulate it when needed to prevent such receptivity by viruses (e.g., HIV). This causes the recovery of cell function which is dependent upon CD4 expression.
  • viruses e.g., HIV
  • the ganglioside composition is topically applied to the skin of a human, particularly the vaginal and rectal areas, to prevent infection of CD4 positive epithelial cells by a virus.
  • topical application is provided prophylatically to the human cells thereby preventing viral infection.
  • This invention relates to humantcells which include selectively modulated CD4 cell-surface determinants, and to a process for inhibiting infection in humans by the human immunodeficiency virus (HIV) .
  • the subject human cells are selectively modulated with a ganglioside composition capable of inducing the rapid and selective disappearance of CD4 cell-surface determinants from human cells. In this way, the receptivity of the modulated human cells to the human immunodeficiency virus is selectively inhibited.
  • EXAMPLE 1 The selective inhibition and disappearance of the expression and function of the CD4 cell-surface determinants on human cells employing a chemical agent comprising a ganglioside composition has been experimentally demonstrated.
  • the mixed ganglioside composition comprised 21% GM. (mono- sialated ganglioside), 40% GD, (di-sialated ganglioside),- 16% CD,, (tri-sialated ganglioside), and 19% GT,. (tetra-sialated ganglioside), having an average molecular weight of 1756 Daltons.
  • the anti CD4 antibody used for this experiment was Leu 3a.
  • the CD3 antibody (Leu 4) was also tested.
  • MFI mean fluorescence intensity
  • the cells were washed twice, stained with optimal concentrations (determined previously) of the various monoclonal antibodies and fluorescein-labeled goat anti-mouse second antibody, washed again, fixed in 1% formalin, and analyzed for MFI after excitation with a 488nm laser light using an Ortho Systems 50 Cytofluorograf.
  • the mononuclear cells were gated on the basis of forward angle and right angle scatter, and the mean fluorescence intensity (MFI) of the stained cell population was determined from a cytogram of 10,000 human cells.
  • the MFI of the ganglioside treated cells were compared to the MFI of untreated cells and the percent inhibition of CD4 expression was established after subtracting MFI of cells stained only with second antibody.
  • Ganglioside inhibition of cell-surface antibody staining was calculated by the following formula: 10
  • the CD4 is induced to disappear 11 as previously described, without effecting the expression and function of the CD3 cell-surface determinants on the same human cells. This is demonstrated in TABLE 1 where cells treated with gangliosides do not change their fluorescence intensity when stained with an antibody compared to another T cell member (defined by the Leu 4 monoclonal antibody).
  • EXAMPLE 2 The high selectivity of the modulation of the expression of CD4 cell-surface determinants by treatment with a ganglioside composition has been experimentally demonstrated.
  • ganglioside composition induced selective loss of the expression of CD4 cell-surface determinants on human T cells, but did not effect the phenotype of any other human cell- surface determinants as recognized By the sp cific monoclonal antibodies listed in that TABLE. Ganglioside pretreatment effected almost equally the staining detected by nine different monoclonal antibodies specific to the CD4 molecule on human T cells.
  • OKT4f (4.6) OKB7, K+L, Ig For HLA-DR, HLA-DQ: For Macrophages:
  • Selective modulation of the expression and function of the CD4 cell-surface determinants on human 13 cells is conducted in the presence of sufficient ganglioside composition to overcome the neutralizing effects of the serum present.
  • One approach is to add an amount of ganglioside which will first neutralize the serum and then will also selectively modulate CD4 cell-surface determinants.
  • Another approach is for the selective modulation of the human cells to be conducted in an area of substantially low blood serum concentration. For example, when this blood serum level was maintained at not more than about 5% by volume, selective modulation was effected.
  • the selective modulation process was conducted in the presence of substantially no blood serum there was a 100% inhibition of the CD4 expression when a lower concentration of gangliosides were used to treat the human cells.
  • the process for " selectively modulating the expression and function of CD4 cell-surface determinants extends generally to all human cells which express CD4, the preferred human cells for selective ' modulation comprise T-helper cells, epithelial cells, and macrophages and brain glial cells, respectively.
  • EXAMPLE 3 The use of ganglioside compositions, but not the individual components of such ganglioside compositions, to selectively modulate CD4 cell-surface determinants has been experimentally demonstrated.
  • T-helper cells were incubated with different concentrations of mixed gangliosides, purified individual gangliosides, modified gangliosides, and ganglioside components, namely, the individual lipid, oligosaccharide, and sialic acid moieties.
  • the activity of gangliosides and ganglioside components on-the expression of CD4 cell-surface determinants was determined. The results are summarized in TABLE 3 below.
  • Lymphocyte populations (10 /ml) were pretreated for one hour at 37°C with varying dilutions of ganglioside compositions, or ganglioside components, prior to staining with anti-CD4 or control antibodies and a fluorascein-labeled second antibody.
  • the staining procedure employed was similar to that used in EXAMPLE 1.
  • ⁇ contained 21% G 1 , 40% CD. , 16% GD ⁇ b , and 19% GT lt) .
  • sialic acids which distinguish gangliosides from other glycosphingolipids, were also necessary 15 components for CD4 modulation, since asialogangliosides and galactocerebrosides, which contained no sialic acids, had no inhibitory activity.
  • the process of this invention also includes the step of maintaining the selected modulation described above by providing continued use in the form of additional amounts of the ganglioside composition provided at a level sufficient to prevent re-expression of: the CD4 cell-surface determinants, i.e., reappearance of the CD4 cell-surface determinants on the human cells.
  • T-helper cells were washed at the end of four hours, twenty-four hours, and forty-eight hours and, after aliquots were removed for staining, the remaining cells were re-suspended in 67uM of gangliosides. The result was 100% inhibition of CD4 expression upon continued use and presence of gangliosides.
  • a process for treating a patient infected with human immunodeficiency virus would comprise the initial step of isolating human blood cells in vitro from the patient as in leukaperesis and lymphocyte harvest and culture, respectively.
  • the isolated human blood cells would then be treated with a 17 chemical agent comprising a ganglioside composition capable of inducing the selective disappearance of said CD4 cell-surface determinants from the human cells by selectively modulating the expression and function of said CD4 cell-surface determinants, and thereby selectively inhibiting the receptivity of the human blood cells by the virus, using the leukapheresis procedure described by Rosenberg, et al.
  • the CD4-modulated human blood cells would be reinfused into the patient.
  • a typical leukapheresis procedure can be conducted as follows:
  • each leukapheresis pack is 300 to 400 ml, which is collected in a Fenwal transfer bag.
  • Mononuclear cells are then separated from neutraphils and erythrocytes using Ficoll-Hypaque density gradients.
  • the separated lymphocytes are harvested, washed twice and resuspended at a concentration of 1- 1.5 x 10 cells/ml in Hank's balanced salt solution containing 75 uM mixed gangliosides, and penicillin, streptomycin sulfate, glutamine, and gentamicin sulfate without additional serum in 1 liter roller bottles.
  • the cells are incubated for 1 hour with continuous rotation at 0.5-1 revolution/min. Aliquots of cells are removed for staining with antibodies to CD3 and CD4 to ascertain the ganglioside effect on CD4 expression.
  • the ganglioside treated cells are centrifuged at 510 x g for 15 minutes in 1 liter bottles, the pellets are pooled in 250 ml centrifuge tubes, and washed twice more in Hank's balanced salt solution without calcium, magnesium, or. phenol red, and the cells are resuspended in infusion medium consisting of 200 ml of 0.9% sodium chloride containing 1% human serum albumen. The final cell suspension is filtered through sterile Nytex and transferred to a Fenwal transer pack.
  • the ganglioside treated cells are administered intravenously through a central venous catheter or into a large peripheral vein. Approximately 10 cells are infused initially, and the remainder are infused 5 minutes later over approximately 20 minutes, with gentle mixing every 5 minutes. No filters are used in the infusion line.
  • EXAMPLE 5 The use of gangliosides to inhibit the infection of CD4 positive target cells by the Human * Immunodeficiency Virus (HIV)-has been demonstrated experimentally.
  • HIV Immunodeficiency Virus
  • H9 or CEM target cells were incubated with either 10% HIV infected cells or supernatants from HIV infected cultures in the presence and absence of gangliosides.
  • aliquots of the infected cells and control cells were counted daily and stained with monoclonal antibodies specific for the gag antigen, which is expressed as a consequence of HIV infection.
  • Other aliquots of cells were stained with anti-CD4 antibody to determine if this molecule had been modulated by the gangliosides.
  • Ten thousand cells from each aliquot were evaluated by flow cytometry as described in EXAMPLE 1 to determine the level of fluorescence intensity of both the gag antigen and CD4.

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EP19880908632 1987-09-22 1988-09-16 Procede de modulation selective de l'expression et de la fonction d'un determinant de surface cellulaire, et production de nouvelles cellules humaines ainsi produites. Withdrawn EP0331716A4 (fr)

Applications Claiming Priority (2)

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US9975387A 1987-09-22 1987-09-22
US99753 1987-09-22

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EP0331716A1 EP0331716A1 (fr) 1989-09-13
EP0331716A4 true EP0331716A4 (fr) 1990-02-06

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EP19880908632 Withdrawn EP0331716A4 (fr) 1987-09-22 1988-09-16 Procede de modulation selective de l'expression et de la fonction d'un determinant de surface cellulaire, et production de nouvelles cellules humaines ainsi produites.

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EP (1) EP0331716A4 (fr)
JP (1) JPH02501534A (fr)
AU (1) AU2523888A (fr)
WO (1) WO1989002918A1 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1239060B (it) * 1990-05-04 1993-09-20 Fidia Spa Processo per la modulazione selettiva dell'espressione e della funzione di un determinante sulla superficie cellulare attraverso appropriati agenti chimici
JPH0416331U (fr) * 1990-05-31 1992-02-10
DE4204907A1 (de) * 1992-02-14 1993-08-19 Reutter Werner Neuartige glykokonjugate mit n-substituierten neuraminsaeuren als mittel zur stimulierung des immunsystems
DE19602108A1 (de) * 1996-01-22 1997-07-24 Beiersdorf Ag Gegen Bakterien, Parasiten, Protozoen, Mycota und Viren wirksame Substanzen
WO2000029556A2 (fr) * 1998-11-17 2000-05-25 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services Identification des glycosphingolipides qui favorisent la penetration du vih-1 dans les cellules
JP3640582B2 (ja) 1999-01-29 2005-04-20 ユニ・チャーム株式会社 フィブリル化レーヨンを含有した水解性繊維シート
JP2001233773A (ja) * 2000-02-22 2001-08-28 Toko Yakuhin Kogyo Kk 抗ウイルス剤

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0058665B1 (fr) * 1980-05-09 1986-02-26 LEFFLER, Hakon Derives d'hydrate de carbone pour inhiber l'adherence bacterienne
US4690915A (en) * 1985-08-08 1987-09-01 The United States Of America As Represented By The Department Of Health And Human Services Adoptive immunotherapy as a treatment modality in humans

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
See also references of WO8902918A1 *
THE JOURNAL OF IMMUNOLOGY, vol. 125, no. 5, November 1980, pages 2106-2111, The Williams & Wilkins Co., US; R.L. WHISLER et al.: "Regulation of lymphocyte responses by human gangliosides" *
THE JOURNAL OF IMMUNOLOGY, vol. 139, no. 10, 15th November 1987, pages 3295-3305, The American Association of Immunologists, US; H. OFFNER et al.: "Gangliosides induce selective modulation of CD4 from helper T lymphocytes" *

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EP0331716A1 (fr) 1989-09-13
WO1989002918A1 (fr) 1989-04-06
JPH02501534A (ja) 1990-05-31
AU2523888A (en) 1989-04-18

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