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WO1993020830A1 - Proteine d'adhesion des monocytes et anticorps monoclonal lie a celle-ci - Google Patents

Proteine d'adhesion des monocytes et anticorps monoclonal lie a celle-ci

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Publication number
WO1993020830A1
WO1993020830A1 PCT/US1993/003433 US9303433W WO9320830A1 WO 1993020830 A1 WO1993020830 A1 WO 1993020830A1 US 9303433 W US9303433 W US 9303433W WO 9320830 A1 WO9320830 A1 WO 9320830A1
Authority
WO
WIPO (PCT)
Prior art keywords
monoclonal antibody
endothelial cells
protein
cells
monocyte
Prior art date
Application number
PCT/US1993/003433
Other languages
English (en)
Inventor
Joan W. Berman
Tina M. Calderon
Original Assignee
Albert Einstein College Of Medicine Of Yeshiva University
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Albert Einstein College Of Medicine Of Yeshiva University filed Critical Albert Einstein College Of Medicine Of Yeshiva University
Publication of WO1993020830A1 publication Critical patent/WO1993020830A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • 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 a method useful in 7he prevention of monocyte invasion of tissues surrounding blood vessels and diseases related
  • monocyte adhesion protein comprises the inducement of a monocyte adhesion protein to the surface of human endothelial cells with specific cytokines, the preparation of a monoclonal antibody which binds to this protein and the formation of an antibody-protein complex.
  • the formation of a complex between the cytokine induced monocyte adhesion protein and the monoclonal antibody decreases the adherence of monocytes to the activated endothelial cells, thereby attenuating or preventing the harmful effects of monocyte adhesion to
  • Monocytes have been implicated in the pathogenesis of atherosclerosis.
  • the binding of monocytes to endothelial cells which, line blood vessel walls is an early event in the development of atherosclerotic lesions.
  • the mechanism by which the monocytes bind to the endothelial cells is unknown.
  • endothelial cells may similarly decrease inflammation.
  • the method of this invention utilizes cytokines to induce a monocyte adhesion protein to the surface of endothelial cells.
  • Cytokines are protein cell regulators, also known as lymphokines, monokines, interleukins and interferons. Cytokines are low molecular weight secreted proteins which are involved in immunity and inflammation, where they regulate amplitude and duration of immunological response. They are usually produced transiently and locally, and interact with high affinity to cell surface receptors specific for each cytokine or cytokine group. Their cell surface binding leads to changes in cellular RNA and protein synthesis culminating in alterations of cell function.
  • the monocyte adhesion protein induced to the cell surface by the cytokines forms a complex with a monoclonal antibody specific for the protein. As a result, monocyte adherence to endothelial cells is decreased.
  • the Newman Patent discloses monoclonal antibodies which bind to proteins on the surface of IL-1 activated endothelial cells, which antibodies do not bind significantly to normal resting endothelial cells and do not bind
  • the monoclonal antibodies disclosed in the Newman Patent are indicated for use in therapeutic compositions for blocking inflammatory responses associated with activated endothelial cells.
  • the Newman Patent discloses four specific monoclonal antibodies designated IE7, 2G7, 7A9 and 3A2.
  • Monoclonal antibody IE7 blocks the binding of T-cells, B-cells, NK cells and monocytes to proteins on the surface of IL-1 activated endothelial cells.
  • Monoclonal antibody IE7 binds to the protein VCAM. Further, proteins to which monoclonal antibody IE7 bind have, under non-reducing conditions on SDS-PAGE, a major band at 99kD and a minor band at 97kD.
  • the IE7 monoclonal antibody binds to proteins on the surface of IL-1-treated endothelial cells which proteins have chronic expression (i.e., have maximal expression on the surface of the endothelial cells for
  • Monoclonal antibody 2G7 of the Newman Patent blocks the binding of T-cells, B-cells and monocytes to proteins on the surface of IL-1-treated endothelial cells.
  • Monoclonal antibody 2G7 also binds to the protein VCAM. Further, monoclonal antibody 2G7 reacts with proteins which, under non-reducing conditions on SDS-PAGE, have a major band at 99kD and a minor band at 87kD.
  • monoclonal antibody 2G7 binds to proteins on the surface of IL-1-treated endothelial cells, which proteins have chronic expression (i.e., have maximal expression for 72-96 hours).
  • Monoclonal antibody 7A9 of the Newman Patent blocks the binding of granulocytes and monocytes to proteins on the surface of IL-1-treated endothelial cells.
  • Monoclonal antibody 7A9 binds to the protein ELAM. Further, the 7A9 monoclonal antibody binds to proteins which, under non-reducing conditions on
  • the 7A9 monoclonal antibody binds to proteins on the surface of IL-1-treated endothelial cells which proteins have chronic expression (i.e., have maximal expression for
  • Monoclonal antibody 3A2 of the Newman Patent binds to proteins which, under non-reducing conditions on SDS-PAGE, show a major band at 177kD and a minor band at 57kD. Further, the 3A2 monoclonal antibody binds to proteins which have acute expression on the surface of IL-1-treated endothelial cells (i.e., the expression of such proteins decreases and disappears by 24 hours).
  • the monoclonal antibodies of the Newman Patent bind to the proteins VCAM and ELAM, which proteins are induced to the surface of endothelial cells with cytokines.
  • the monoclonal antibody of the present invention does not bind to either VCAM or ELAM. Instead, the monoclonal antibody binds to a different monocyte adhesion protein.
  • This invention relates to the inducement of a monocyte adhesion protein to the surface of human endothelial cells by activation of the endothelial cells with specific cytokines, the preparation of a monoclonal antibody which binds to this protein and the formation of an antibody-protein complex.
  • the cytokine-induced monocyte adhesion protein on the surface of the endothelial cells and the monoclonal antibody thereto react to form a complex, the adherence of monocytes to the endothelial cells is decreased.
  • the monocyte adhesion protein recognized by the monoclonal antibody is not cell surface proteins VCAM or ELAM.
  • Figure 1 represents expression of the IG9 monocyte adhesion protein on the surface of TNFa treated endothelial cells
  • Figure 2 represents expression of the IG9 monocyte adhesion protein on the surface of TNFa treated endothelial cells as detected by ELISA
  • Figure 3 represents the binding of various preparations of monoclonal antibody IG9 to TNFa treated endothelial cells, and thereby shows that the IG9 monoclonal antibody inhibits U937 monocyte cell adherence to the TNFa treated endothelial cells;
  • Figure 4 represents the binding of monoclonal antibody IG9 to the IG9 monocyte adhesion protein, compared with the binding of the Newman Patent monoclonal antibodies IE7 and 2G7 to the protein VCAM as shown by ELISA;
  • Figure 5 represents the binding of monoclonal antibody IG9 to the IG9 monocyte adhesion protein, compared with the binding of the Newman Patent
  • Figure 6 represents the binding of monoclonal antibody IG9 to the IG9 monocyte adhesion protein, compared with the binding of monoclonal antibody 3B7, which recognizes the same protein as the Newman Patent monoclonal antibody 7A9, to the protein ELAM as shown by immunoprecipitation;
  • Figure 7 represents the reactivity of monoclonal antibody IG9 with endothelial cells lining a blood vessel in a tissue section of human lung with extensive inflammation;
  • Figure 8 represents the reactivity of monoclonal antibody IG9 with endothelial cells overlying a human atherosclerotic plaque
  • Figure 9 represents the reactivity of monoclonal antibody IG9 with the endothelial cells overlying an atherosclerotic plaque where there is lesion involvement;
  • Figure 10 represents the reactivity of monoclonal antibody IG9 with endothelial cells overlying an atherosclerotic plaque in the aorta of a WHHL rabbit; and
  • Figure 11 represents the reactivity of monoclonal antibody IG9 with endothelial cells lining an arterial vessel in a healing human myocardial infarction.
  • Monocyte adherence to the endothelial cell lining of blood vessels has been implicated in the pathogenesis of atherosclerosis and other diseases, including disseminated intravascular coagulation
  • DIC DIC
  • monocyte invasion of tissues surrounding blood vessels can be reduced or eliminated, atherosclerosis, DIC and other diseases similarly provoked may be attenuated in their initial stages, and possibly reduced altogether.
  • monocytes bind with endothelial cells which line blood vessel walls.
  • the purpose of this invention is to reduce or prevent the binding of monocytes to endothelial cells, and to treat and prevent diseases caused by monocyte adherence to endothelial cells and their migration into surrounding tissue.
  • this invention may serve to reduce inflammation.
  • the invention comprises inducing a monocyte adhesion protein to the surface of human endothelial cells with specific cytokines.
  • Cytokines which may be used for this purpose are TNFa, IL-1a and IL-1 ⁇ . However, it is possible that other cytokines may also be used for this purpose.
  • This invention further comprises producing a monoclonal antibody to the monocyte adhesion protein and forming an antibody-protein complex.
  • the monoclonal antibody and the monocyte adhesion protein on the surface of the endothelial cells form a complex, the ability of monocytes to adhere to the endothelial cells upon which the complex exists is decreased. This decrease in the adherence of
  • monocytes to activated endothelial cells may result in a reduction of hemorrhage, inflammation, and attenuation of the initial stages of atherosclerosis, DIC and other diseases provoked by monocyte adherence to endothelial cells and their subsequent migration into surrounding tissues.
  • this complex prevents monocytes from adhering to activated endothelial cells, it does not prevent the adherence of T-cells, B-cells, NK cells, granulocytes, lymphocytes or other white blood cells to such activated endothelials.
  • Endothelial cells were harvested from human umbilical veins and maintained in tissue
  • the cells were grown to confluency in gelatin-coated 100 mm tissue culture dishes (Falcon Labware, Oxnard, CA) and maintained at 37oC and 5% CO 2 .
  • the cell culture medium contained Medium 199
  • heparin (Sigma Chemical Company, St. Louis, MO), 10% human and 20% newborn calf serum (Gibco), 1.5 mM glutamine (Sigma Chemical Company) and 3 mg% partially purified acidic fibroblast growth factor extracted from bovine brain.
  • Cell type was confirmed by the typical cobblestone morphology observed in tissue culture and by the presence of Von Willebrand factor antigen.
  • the medium was removed from the cells and replaced with fresh medium containing TNFa (100 units/ml).
  • the cells were then incubated at 37°C, 5% CO 2 for 5 hours to induce the monocyte adhesion protein to the surface of the endothelial cells.
  • TNFa the cells were collected by gentle scraping, pelleted, and half of the cells were fixed with 0.1% glutaraldehyde.
  • cytokines which may be used to induce the monocyte adhesion protein to the surface of endothelial cells are IL-1a and IL-1 ⁇ , with
  • mice (BALB/c F) were injected intraperitoneally with a 1:1 mixture of fixed and unfixed cells (10 7 total) in saline. The procedure was repeated twice, every other week. One week after the last boost, the sera of the animals was tested for reactivity to TNFa treated endothelial cells by
  • the animal with the highest titered serum was again boosted intraperitoneally, and 2 days later its spleen was removed for fusion with NSO myeloma cells.
  • the fusion of the antibody-producing B-lymphocytes from the spleen with the NSO myeloma cells resulted in a
  • monoclonal antibody IG9 which monoclonal antibody is reactive with the monocyte adhesion protein (IG9 monocyte adhesion protein) which was induced to the surface of the endothelial cells with TNfa.
  • IG9 monocyte adhesion protein monocyte adhesion protein
  • the endothelial cells were plated onto 96 well collagen-coated microtiter dishes, and at confluence, the cells were treated with 100 ml TNFa for 5 hours. The cultures were then washed and fixed in 0.1% glutaraldehyde. Hybridoma culture supernate (100 Ul) was added to each well for 90 minutes at 37°C. After several washes, a mixture of alkaline
  • the endothelial cells were then plated onto collagen-coated LAB-TEK four chamber slides. After 24 hours, they were treated with TNFa (100 units/ml) for varying amounts of time, and were washed and fixed with 1% formaldehyde. The cells were then treated with 200 ml of culture supernate or purified antibody (1:500), with fluoresceinated GAMIG and were examined microscopically.
  • the IG9 monocyte adhesion protein under non-reducing conditions on SDS-PAGE, has a major band at 105kD and a minor band at 57kD.
  • the IG9 protein appears on the surface of activated endothelial cells after 3 hours, is maximally expressed for 4-9 hours, declines at 24 hours and is undetectable at 48 hours. This protein is neither VCAM nor ELAM, which proteins have been previously identified on the surface of cytokine-activated endothelial cells.
  • This protein is recognized on activated endothelial cells which line blood vessels where there is inflammation and/or atherosclerotic plaque (see Figures 7 and 8), on coronary artery endothelium overlying atherosclerotic plaque where there are lesions (see Figure 9), in WHHL rabbit aorta where there is atherosclerotic plaque
  • the prepared IG9 monoclonal antibody to the IG9 monocyte adhesion protein which is an IgG, isotype antibody, blocks the adhesion of the human promyelomonocytic cell line, U937, to TNF treated endothelial cells by 35-40%, and has no effect on U937 cell binding to untreated endothelial cells.
  • This monoclonal antibody does not block T-cell, B-cell, NK cell, lymphocyte or granulocyte adhesion to TNF treated endothelial cells.
  • the IG9 is an IgG, isotype antibody
  • the monoclonal antibody does not bind to resting endothelial cells, resting monocytes, tissue fibroblasts, smooth muscle cells, mononuclear cells, or alveolar macrophages.
  • the IG9 monoclonal antibody does bind to TNF activated endothelial cells, IL-1 activated endothelial cells and lipopolysaccharide activated endothelial cells.
  • This antibody while binding to the IG9 monocyte adhesion protein of this invention, does not bind to either VCAM or ELAM proteins, which proteins may also be induced to the surface of endothelial cells with cytokines. Both the
  • IG9 monocyte adhesion protein and the IG9 monoclonal antibody appear to be involved specifically in monocyte-endothelial cell interactions.
  • Figure 1 shows endothelial cell surface localization of the IG9 monocyte adhesion protein as detected by electron microscopy.
  • HUVE plated on gelatin-coated 4 chamber Lab-Tek slides were treated with medium-containing TNFa (100 U/ml) for 24 hours, fixed with 2% paraformaldehyde, 0.25% glutaraldehyde and incubated with IG9 monoclonal antibody supernatant followed by biotinylated goat anti-MIG and
  • streptavidin particles The small dark particles on the cell surface of a TNFa treated HUVE cells can be seen in this electron micrograph and illustrate the even distribution of the IG9 monocyte adhesion protein on the activated endothelial cell membranes.
  • Figure 2 shows the expression of the IG9 monocyte adhesion protein on the surface of TNFa treated endothelial cells as detected by ELISA.
  • HUVE plated on gelatin-coated 96-well plates were treated with medium containing TNFa (100 U/ml) for varying periods of time. Cell surface expression was detected using the IG9 monoclonal antibody supernatant after fixation of the HUVE with 1% formaldehyde in PBS.
  • Figure 2 also shows the amount of time required for expression of the IG9 monocyte adhesion protein on the surface of the activated endothelial cells, which was 3 hours.
  • FIG. 3 shows the binding of various preparations of the IG9 monoclonal antibody to TNFa treated endothelial cells.
  • MED is the medium used wherein HUVE were treated with medium alone before the adhesion of the U937 monocyte cells. Since there was no antibody present in the medium, the percent adherence was the control value, and the inhibitory effect of the different antibody preparations on U937 cell adherence was compared to this control value.
  • IG9-S is the hybridoma supernatant from cells making the IG9 monoclonal antibody. This preparation contained approximately 0.05 mg/ml antibody.
  • IG9-P indicates that the IG9 monoclonal antibody was purified from hybridoma supernatant by passage through Bakerbond ABx Prepscale (J.T. Baker, Phillipsburg, New Jersey) columns. This preparation contained approximately 0.4 mg/ml antibody.
  • IG9-A is the ascites fluid from mice injected with the IG9
  • IG9-F(ab') 2 is where ascites were used to isolate F(ab') 2 fragments after pepsin digestion. This preparation contained approximately 0.36 mg/ml antibody and did not contain the Fc portion of the IG9 monoclonal antibody, which may contribute to the non-specific interaction of antibodies with endothelial cells.
  • Neg Ab is two different monoclonal antibodies that did not react with HUVE . These were used as negative control antibodies. These were included in the U937 cell adhesion assay to show that the inhibition of adhesion by the IG9 monoclonal antibody was not a non-specific event mediated by any antibody.
  • Figure 3 shows that the IG9 monoclonal antibody inhibits U937 monocyte cell adherence to the TNFa treated endothelial cells.
  • Figure 4 represents the binding of monoclonal antibody IG9 to the IG9 monocyte adhesion protein. It also compares the binding of the Newman Patent antibodies IE7 and 2G7 to the protein VCAM. VCAM was expressed at a much later time than the IG9 protein. This shows that the IG9 protein is not VCAM, and that the IG9 monoclonal antibody, which binds to the IG9 protein and not to VCAM, is different than the IE7 and 2G7 monoclonal antibodies. This is shown by ELISA.
  • Figure 5 shows the binding of monoclonal antibody IG9 to the IG9 monocyte adhesion protein. The binding is also compared with the binding of the Newman Patent monoclonal antibody 2G7 to the protein VCAM. This is shown by immunoprecipitation.
  • the proteins on the surface of the HUVE cells treated with TNFa for 8.5 hours were labeled with 125I followed by detergent solubilization of the cells. This protein lysate was divided into five equal aliquots.
  • Lane C shows the immunoprecipitation of one aliquot with the IG9 antibody
  • lane D shows an immunoprecipitation with the 2G7 antibody
  • Lane E shows an immunoprecipitation with a negative control antibody.
  • lanes A and B two aliquots of protein lysate were pre-cleared twice with antibody 2G7. One aliquot was then immunoprecipitated with the IG9 antibody (lane A), and the other was immunoprecipitated with the 2G7 antibody (lane B).
  • Pre-clearing with the 2G7 antibody removed all of the protein recognized by this antibody so that a
  • Figure 6 shows the binding of monoclonal antibody IG9 to the IG9 monocyte adhesion protein of the invention. It compares such binding with the binding of monoclonal antibody 3B7 to the protein ELAM as shown by immunoprecipitation. Monoclonal antibody 3B7 recognizes the same protein as the Newman Patent monoclonal antibody 7A9. To perform this immunoprecipitation, HUVE cells were treated with a medium containing TNFa (100 U/ml) for 5 hours, and cell surface proteins were iodinated with 125 I-Na followed by detergent solubilization. The labeled
  • HUVE protein lysate was divided into four aliquots.
  • Chimeric antibodies which contain mouse variable region sequences joined to human constant regions may be genetically engineered using the murine IG9 monoclonal antibody of this invention. Once the IG9 mouse monoclonal antibody is sequenced, the DNA encoding the mouse variable region, which comprises the antigen binding site, can be ligated to DNA encoding human constant regions and this construct can be inserted into an immunoglobulin expression vector.
  • This chimeric antibody may be injected into humans to attenuate or prevent the harmful effects of monocyte adhesion to endothelial cells and their subsequent migration into surrounding tissues.
  • IL-1-induced inflammation in the rabbit retina was used as a model.
  • the IG9 monoclonal antibody isolated by the procedure outlined in EXAMPLE #1 was injected intraperitoneally into a rabbit at the same time as the intraocular injection of IL-1 and a few times during the following 6 or 24 hours.
  • the results of the injections of the IG9 antibody showed a marked decrease in the inflammatory responses normally seen when IL-1 is injected in the rabbit retina.
  • the number of monocytes in and around the retinal blood vessels were reduced and vascular permeability was greatly decreased.
  • the IG9 antibody recognized the protein induced on the surface of the endothelial cells lining the retinal blood vessels of the rabbit after they were exposed to
  • IL-1 IL-1.
  • monocyte binding to the endothelial cells lining the retinal blood vessels is reduced and therefore migration into the surrounding tissue area is also reduced. This results in a decrease in the normal inflammatory responses elicited by the injection of IL-1 as well as a decrease in IL-1 induced vascular permeability.
  • Example #1 The monoclonal antibody isolated by the procedure outlined in Example #1 was tested for reactivity with endothelial cells lining vessels with evidence of atherosclerotic lesions.
  • Figure 7 shows the reactivity of the IG9 monoclonal antibody with endothelial cells lining a blood vessel in a tissue section of human lung with extensive inflammation. A paraffin-embedded tissue section was analyzed by immunoalkaline phosphatase staining. The endothelial cells lining the vessel exhibited strong reactivity with the IG9 monoclonal antibody.
  • Figure 8 represents the reactivity of the IG9 monoclonal antibody with endothelial cells overlying a human atherosclerotic plaque.
  • a complex atherosclerotic plaque from a human coronary artery exhibited monoclonal antibody IG9 ascites reactivity with the endothelial cells (see arrow).
  • Figure 9 represents the reactivity of monoclonal antibody IG9 with the endothelial cells overlying an atherosclerotic plaque where there is lesion involvement.
  • a critically narrowed human coronary artery with asymmetrical, complex atherosclerotic plaque (P) exhibited specific endothelial cell reactivity in areas of lesion involvement.
  • Sections of coronary arteries representing a range of lesion involvement from 17 different individuals were analyzed. Vessels with any evidence of pathology in each of the cases examined were reactive with the IG9 monoclonal antibody, while uninvolved vessels were unreactive.
  • FIG. 10 represents the reactivity of monoclonal antibody IG9 with endothelial cells overlying an atherosclerotic plaque in the aorta of a WHHL rabbit.
  • the rabbit may therefore provide an animal model in which the role of the monocyte adhesion protein on endothelial cells in the development of atherosclerosis in vivo may be studied and determined.
  • FIG. 11 represents the reactivity of monoclonal antibody IG9 with endothelial cells lining an arterial vessel in a healing human myocardial infarction. There was intense endothelial reactivity with monoclonal antibody 1G9 (see arrow).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

L'invention se rapporte à un procédé destiné à la prévention de l'adhérence des monocytes sur les vaisseaux sanguins qui recouvrent les cellules endothéliales, de l'invasion par les monocytes des tissus environnants, et des maladies connexes. Ce procédé consiste à induire une protéine d'adhésion monocytaire à la surface des cellules endothéliales par un traitement aux cytokines spécifiques, à préparer un anticorps monoclonal qui se lie à la protéine d'adhésion des monocytes, et à mettre en contact l'anticorps avec la protéine pour former un complexe. L'anticorps monoclonal ne se lie pas aux protéines VCAM ou ELAM des surfaces cellulaires. Le complexe a pour effet de réduire l'adhérence des monocytes aux cellules endothéliales, et atténue et prévient, de cette façon, les effets dangereux de l'invasion monocytaire sur les cellules endothéliales et les tissus environnants.
PCT/US1993/003433 1992-04-16 1993-04-12 Proteine d'adhesion des monocytes et anticorps monoclonal lie a celle-ci WO1993020830A1 (fr)

Applications Claiming Priority (2)

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US86992492A 1992-04-16 1992-04-16
US07/869,924 1992-04-16

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WO1993020830A1 true WO1993020830A1 (fr) 1993-10-28

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) * 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5011778A (en) * 1989-05-23 1991-04-30 Otsuka Pharmaceutical Co., Ltd. Monoclonal antibodies directed to IL-1 activated endothelial cells and medicaments employing the monoclonal antibodies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) * 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5011778A (en) * 1989-05-23 1991-04-30 Otsuka Pharmaceutical Co., Ltd. Monoclonal antibodies directed to IL-1 activated endothelial cells and medicaments employing the monoclonal antibodies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
IMMUNOLOGY, Vol. 59, issued 1986, MACDONALD et al., "A Monoclonal Antibody Recognizing the p150/95 Leucocyte Differentiation Antigen", pages 427-431. *

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