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WO1996022785A1 - Procedes pour le traitement d'une lesion pulmonaire aigue induite par le syndrome de mendelson - Google Patents

Procedes pour le traitement d'une lesion pulmonaire aigue induite par le syndrome de mendelson Download PDF

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Publication number
WO1996022785A1
WO1996022785A1 PCT/US1996/001150 US9601150W WO9622785A1 WO 1996022785 A1 WO1996022785 A1 WO 1996022785A1 US 9601150 W US9601150 W US 9601150W WO 9622785 A1 WO9622785 A1 WO 9622785A1
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lung
group
term
treatment
long
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PCT/US1996/001150
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English (en)
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Virginia C. Broaddus
Michael A. Matthay
Hans G. Folkesson
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The Regents Of The University Of California
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Priority to JP8523042A priority Critical patent/JPH10512278A/ja
Priority to AU47716/96A priority patent/AU4771696A/en
Priority to EP96903731A priority patent/EP0806962A4/fr
Publication of WO1996022785A1 publication Critical patent/WO1996022785A1/fr

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    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a method for treating and protecting patient lungs exposed to acid resulting from the aspiration of gastric contents or other causes.
  • the aspiration of gastric acid can occur, for example, when an unconscious patient regurgitates the stomach contents into the lungs.
  • Acid aspiration is the second leading cause of the adult respiratory distress syndrome (ARDS) , a syndrome which is characterized by injury to the pulmonary endothelium and the alveolar epithelium with leakage of blood and plasma into the interstitial and intra-alveolar spaces.
  • ARDS adult respiratory distress syndrome
  • the mortality from acid-induced ARDS range from 40% to 50%. No adequate treatments are presently available.
  • Mulligan et al. (1993) J. IMMUNOL. 150:5585 describes the use of anti-IL-8 antibodies to treat immunologically induced lung inflammation. Sekido et al . (1993) NATURE 365:654 shows that anti-IL-8 antibodies are able to reduce reperfusion injuries in ischemic lung tissue in rabbits. Anti-IL-8 antibodies have been shown to inhibit neutrophil influx in an endotoxin-induced pleurisy model in rabbits. Broaddus, et al . (1994) J. IMMUNOL. 152:2960-2967. Elevated levels of IL-8 are present and cause neutrophil influx in patients suffering from adult respiratory distress syndrome. Miller et al .
  • IL-8 has been proposed as a major chemotactic factor for recruitment of neutrophils to extravascular sites of inflammation, including those in the lungs.
  • the magnitude of acute lung injury following acid aspiration is reduced or eliminated by the systemic administration of an interleukin-8 (IL-8) -binding substance to the patient.
  • the IL-8-binding substance is selected to neutralize free-IL-8 released from cells exposed to the acid.
  • the neutralization of IL-8 inhibits or prevents influx of neutrophils from circulation into the extravascular space of the lung, and it is believed that reduction of neutrophil recruitment by the IL-8-binding substance lessens the cellular damage.
  • the exemplary IL- 8-binding substance is anti-IL-8 antibody.
  • the IL-8- binding substance is administered to the patient as rapidly as possible following acid aspiration, but such administration can be delayed for as long as one hour without a substantial loss of therapeutical effectiveness.
  • Figs. 1A and IB Alveolar-arterial oxygen tension difference in the positive control, pretreatment, treatment, and negative control groups over 6 h (Fig. 1A) and over 24 h (Fig. IB) .
  • the alveolar-arterial oxygen tension difference in the pretreatment and treatment groups was significantly less than that in the positive control group from 2 h onwards and was no different from that in the negative control group.
  • the alveolar-arterial oxygen tension difference was significantly less in the treatment (long-term) group than in the positive control
  • Figs. 3A and 3B Endothelial permeability in the lung measured as the accumulation of the vascular protein tracer, 131 I-albumin, in the extravascular spaces of the lung and expressed as extravascular plasma equivalents in the positive control, pretreatment, treatment, and negative control groups at 6 h (Fig. 3A) , and in the positive control (long-term) group at 12-14 h and the treatment (long-term) group at 24 h (Fig. 3B) . In the short-term studied, the extravascular plasma equivalents were decreased by 70% in the pretreatment and treatment groups compared to the positive control group at 6 h.
  • the number of neutrophils was 50% lower in the pretreatment and treatment groups than in the positive control group and no different from that in the negative control group at 6 h.
  • the number of neutrophils was more than 75% lower in the treatment (long-term) group at 24 h than in the positive control (long-term) group at 12-14 h.
  • Data are means ⁇ SD, * p ⁇ 0.05 versus the positive control group (Fig. 4A) or the positive control (long-term) group (Fig. 4B) .
  • the present invention is based at least in part on the discovery that acid-induced lung injury is mediated by neutrophils recruited to the lung by interleukin-8 (IL-8) -dependent mechanisms. It is believed that direct injury of the lung from the aspirated gastric acid is limited in extent, perhaps because the acid is rapidly neutralized after entering the lungs. Acid aspiration, however, stimulates the release of substantial quantities of IL-8 into the airspaces from a variety of cells in the lung, including airway epithelial cells, alveolar epithelial cells, and alveolar macrophages.
  • IL-8 interleukin-8
  • IL-8 is believed to diffuse toward the pulmonary endothelium, thereby establishing a chemotactic gradient for neutrophils and possibly binding to the luminal endothelial surface where the IL-8 could interact with circulating neutrophils.
  • the interaction of IL-8 with neutrophils then induces up regulation of neutrophil adhesion molecules on the endothelium, neutrophil migration through the activated endothelium, and priming of neutrophils for activations by other mechanisms.
  • Neutrophils recruited to the lung in this manner are believed to be responsible for most of the endothelial injury that results in formation of a protein-rich pulmonary edema fluid that is characteristic of acid- aspiration acute lung injury.
  • the present invention relies on the binding of free IL-8 released from acid-stimulated airway epithelial cells, alveolar epithelial cells, and alveolar macrophages. Binding preferably occurs through a region of the IL-8 molecule which binds to the IL-8-receptor on the neutrophils, thus directly blocking binding and recruitment of the neutrophils by the released IL-8. Binding should occur with an affinity of at least about 10 7 M '1 , preferably at least 10 8 M "1 .
  • Suitable binding substances for inhibiting binding between IL-8 and circulating neutrophils include anti-IL-8 antibodies, and fragments thereof; an IL-8- receptor protein, or fragment or analogue thereof; or any other protein, glycoprotein, carbohydrate, small molecule, or the like, which is able to disrupt binding between the released IL-8 and the circulating neutrophils.
  • the IL-8-binding substance will preferably bind to the IL-8 molecule at or adjacent to the region on the molecule which binds to the IL-8-receptor on the neutrophils. By binding directly to this region, all interaction between the IL-8 molecule and the neutrophil will be blocked. By binding close to this region, sufficient stearic hinderance may be provided in order to effectively inhibit neutrophil recruitment by the released IL-8.
  • the presently preferred IL-8-binding substance is neutralizing antibody to the IL-8 molecule.
  • neutralizing it is meant that the antibody will be able to neutralize, i.e. inhibit, binding between the IL- 8 molecule and the circulating neutrophils.
  • Such antibodies may be prepared by employing IL-8, or an IL-8- fragment, as an immunogen in conventional techniques for preparing polyclonal or monoclonal antibodies. Such techniques are well described in the scientific and patent literature. See, for example, .Antibodies : A LABORATORY MANUAL, Harlow and Lane Eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (1988) .
  • the IL-8-binding substance will be systemically, usually intravenously, administered to the patient as quickly as possible after occurrence of the acid aspiration.
  • the total dosage may vary from 1 ⁇ g/kg of body weight to 10 mg/kg of body weight.
  • the dosage will typically vary from 1 mg/kg to 10 mg/kg, with the total dosage being administered continuously, as a single bolus or as multiple boluses over time. While intravenous administration is preferred, the IL-8 binding substance could be administered by other systemic routes, such as intratracheally.
  • the IL-8-binding substance will be incorporated into a suitable pharmaceutical composition including the desired dosage of the binding substance.
  • a suitable pharmaceutical composition including the desired dosage of the binding substance.
  • Such compositions will usually include a pharmaceutically acceptable carrier, which can be any compatible, non-toxic substance suitable to deliver the IL-8-binding substance to the patient. Sterile water, alcohol, fats, waxes, and inert solids, may be used as the carrier. Pharmaceutically acceptable adjuvants, buffering agents, and the like, may also be incorporated into the pharmaceutical compositions.
  • Such compositions will be suitable for parenteral administration, i.e. intravenous or for pulmonary
  • a 22-gauge Angiocath ® was inserted in the marginal ear vein for administering fluid and drugs .
  • a PE-90 catheter was inserted in the right carotid artery to monitor systemic blood pressure and to obtain blood samples.
  • a 4.0 mm ID endotracheal tube was inserted through a tracheostomy.
  • the rabbits were maintained in the prone position during the experiments and ventilated with a constant-volume piston pump (Harvard Apparatus Co., Dover, MA., USA) with an inspired oxygen fraction of 1.0 and with a peak airway pressure of 15-18 cm H 2 0 during the baseline period, and supplemented with a positive end-expiratory pressure of 4 cm H 2 0.
  • the respiratory rate was adjusted to maintain the arterial PC0 2 between 35-40 mm Hg. Thereafter, the ventilator settings were kept constant throughout the experiment .
  • a solution of 100 mOsm/kg of NaCl (1/3 normal saline) was prepared with isotonic 0.9% saline and distilled water. The 1/3 normal osmolality was chosen to match the osmolality of gastric aspirates. Then, hydrochloric acid (HCl) was added to the solution and titrated to a pH of 1.5. In the negative control studies, 1/3 normal saline was used as the instillate. Evans blue dye (1 mg, Aldrich Chemical Company Inc., Milwaukee, WI . , USA) was added to all instillates in order to confirm at post-mortem examination that the instilled fluid was distributed equally to both lungs.
  • ARIL8.2 did cross-react with human IL-8, but not with closely related cytokines (hMGSA, platelet factor-4, ⁇ -thromboglobulin) , other human cytokines (IL- 1 / 3, TNF- ⁇ ) , or other chemotactic factors (FMLP, C5a) .
  • the antibody preparation was sterile filtered and endotoxin was undetectable by Limulus assay.
  • a tubing (5 Fr., Accumark ® Premarked Feeding Catheter, Concord/Portex, Keene, NH., USA) was gently passed through the tracheal tube until is was placed approximately 1 cm above the carina. Then, HCl or 1/3 normal saline (4 ml/kg body weight) was instilled into both lungs over 3 minutes. After the instillation was completed, the tubing was withdrawn.
  • the abdomen was opened and the rabbit was exsanguinated by transection of the abdominal aorta.
  • the lungs were removed through a median sternotomy.
  • An alveolar sample was aspirated via sampling catheter gently passed through the trachea to a wedged position in a distal airway.
  • the left lung was clamped at the main bronchus for later use in extravascular lung water and tracer protein measurements (see below) .
  • the right lung was then lavaged 2 times, using 6 ml of isoosmolar 0.9% NaCl containing 12 ⁇ M lidocaine (Sigma Biochemicals, St. Louis, MO., USA) each time.
  • the radioactivity of the samples was measured. Total and differential cell counts were measured on the blood and bronchoalveolar lavage samples. The cells were counted as cells per ml lavage and then multiplied by the lavage column used (12 ml) . Free, unbound IL-8 concentrations were measured in the plasma samples and the alveolar samples.
  • TCA trichloracetic acid
  • the rabbits received either 0.9% NaCl (2 ml/kg body weight) or an irrelevant monoclonal antibody (2 mg/kg body weight) intravenously.
  • the irrelevant monoclonal antibody was of the same isotype as ARIL8.2 (IgG2a) and directed against the gpl20 envelope protein on the human immunodeficiency virus. Because there were no differences in the studied parameters, the rabbits given the irrelevant monoclonal antibody and those given NaCl intravenously were combined into one group.
  • the rabbits received the monoclonal antibody against IL-8 (ARIL8.2, 2 mg/kg body weight) intravenously.
  • the rabbits received ARIL8.2 (2 mg/kg body weight) intravenously.
  • the heart rate, systemic blood pressure, and airway pressure were measured using calibrated pressure transducers (Pd23 ID, Gould Oxnard, CA. , USA) and recorded continuously on a Grass polygraph (Grass Model 7 Polygraph, Grass Instruments, Quincy, MA., USA) . Arterial blood gases and pH and the systemic arterial pressure were measure every 30 minutes. The alveolar- arterial oxygen difference was calculated.
  • Extravascular Lung Water Our method for the determination of extravascular lung water has been described previously in detail. Berthiaume et al . (1987) J. CLIN. INVEST. 79:335- 343, and Wiener-Kronish et al . (1991) J. CLIN. INVEST. 88:864-875.
  • the left lung was homogenized and the extravascular lung water was determined by measuring the extravascular water-to-dry weight ratio (gram water/gram dry lung) . Because the right lung was lavaged for cell counts, the data for extravascular lung water was obtained for the left lung only. The bronchoalveolar lavage from the right lung and the homogenates from both lungs were used for measurement of radioactivity (see below) .
  • Lung Vascular Permeability For measurement of lung endothelial permeability to protein, the clearance of the vascular tracer protein, 131 I-albumin, across the endothelium into the extravascular compartments of the lungs was measured. The total extravascular 131 I-albumin accumulation in the lung was calculated by taking the total lung 131 I-albumin
  • 131 I- albumin in the vascular space was calculated by multiplying the counts in the final plasma sample by the calculated plasma volume in the lungs, as we have done previously. Berthiaume et al . (1987) J. CLIN. INVEST. 79:335-343, and Wiener-Kronish et al. (1991) J. CLIN. INVEST. 88:864-875. The extravascular accumulation of 131 I- albumin in the lung was expressed as plasma equivalents, or the milliliters of plasma that would account for the radioactivity in the lung.
  • an ELISA when detecting antigen in the presence of a soluble antibody identical to the capture antibody, an ELISA can be nonlinear at increasing dilutions, perhaps because antigen dissociates from the solutable antibody and is subsequently bound by the capture antibody. Therefore, for the neutralized samples, we chose the lowest dilution (1:10) for quantitating free IL-8, knowing that this may still be an overestimate of the free IL-8 present.
  • we tested the ELISA with standards of rrIL-8 mixed with ARIL8.2 we found that, as ARIL8.2 concentrations increased, the free IL-8 detected decreased until, at a molar ratio of 5:1 and higher (mAb:IL-8) , no IL-8 could be detected. All samples were coded so that the experimental condition was not known by the individual doing the assays.
  • One-way ANOVA with repeated measurements analysis was used to compare samples obtained at several time points from the same animal.
  • One-way ANOVA (factorial) was used when comparing other single groups.
  • Student-Newman-Keuls test was used as a post-hoc statistical test. Values are expressed as either mean ⁇ SD or mean ⁇ SEM as indicated in tables and figure legends.
  • the data from the HCl instilled rabbits pretreated with either the irrelevant monoclonal antibody, anti-gp 120, or with saline were combined because there were no significant differences between the groups.
  • Data are means ⁇ SD p ⁇ 0.05 versus baseline t p ⁇ 0.05 versus positive control group
  • the rabbits died wit severe hypoxemia between 12-14 h.
  • the rabbits lived for 24 h withou hypoxemia .
  • the extravascular lung water (water-to-dry weight ratio) in the pretreatment and treatment groups was 35% lower than in the positive control group and not significantly different from that in the negative control group at 6 h
  • the extravascular accumulation of plasma equivalents in the lungs of the pretreatment and treatment groups was 70% lower than in the positive control group at 6 h (Fig. 3A) , although the extravascular accumulation of plasma was significantly higher than in the negative control group.
  • the extravascular accumulation of plasma equivalents in the lung was 75% lower in the treatment (long-term) group at 24 h than in the positive control (long-term) group at 12-14 h (Fig. 3B) .
  • the number of polymorphonuclear leukocytes (PMN) lavaged from the air spaces in the pretreatment and treatment groups was more than 50% lower than in the positive control group and no different from that in the negative control group (Fig. 4A) .
  • the number of lavaged neutrophils in the treatment (long-term) group at 24 h was more than 75% lower than in the positive control
  • the concentrations of free IL-8 in the final alveolar fluid samples were more than 10-fold lower in the pretreatment and treatment groups than in the positive control group at 6 h (Table 3) . Because no undiluted alveolar fluid could be aspirated in the negative control group, free IL-8 was also measured in bronchoalveolar lavage fluid. As was the case in the alveolar fluid, free IL-8 concentrations in the lavage fluid were more than 10-fold lower in the pretreatment and treatment groups than in the positive control group (Table 3) . Of interest, the free IL-8 in lavage fluid in the treatment group was not different from the negative control group (Table 3) .
  • alveolar fluid could not be aspirated from the treatment (long-term) group.
  • the free IL-8 concentrations were significantly lower in the treatment (long-term) group than in the positive control (long-term) group (Table 3) .
  • the concentration of immunoreactive free IL-8 (not bound by the anti-IL-8 monoclonal antibody,
  • ARIL8.2 was low at all times and similar for all groups
  • the role of the neutrophil in injuring the lung was supported by the marked reduction of lung injury after neutrophil depletion.
  • the role of IL-8 in mediating the recruitment of neutrophils and the resultant lung injury following acid instillation was established by neutralizing IL-8.
  • the anti-I -8 antibody effectively reduced the concentrations of free IL-8 to less than 10% of the concentration in the positive control (acid-instilled) rabbits, to a level at the lower limit of the biological activity of IL-8 in both in vi tro and in vivo studies. This IL-8 concentration was probably close to that in the negative control (saline- instilled) rabbits, as judged by the similar IL-8 concentrations in the bronchoalveolar lavage fluid.
  • the use of the anti-IL-8 monoclonal antibody led to a more than 50% decrease in the neutrophil influx and, more importantly, to a dramatic reduction in the severity of the acute lung injury due to acid aspiration. Following neutralization of IL-8, the acid-induced abnormalities in gas exchange, extravascular lung water, and lung vascular permeability were nearly completely prevented.
  • the water-to-dry weight ratio of 7.0 g water/g dry lung at 6 h and 8.0 g water/g dry lung at 12-14 h clearly indicates significant alveolar edema. These differences become more obvious when the lung water is expressed as the calculated milliliters of water accumulated in the lung in excess of that in a normal rabbit lung (3.2 g water/g dry lung) .
  • the excess water in both lungs was approximately 9.2 ml, or more than three-fold higher than the amount (1.6-2.6 ml) in the negative control, pretreatment and treatment groups.
  • TNF- ⁇ is a major proximal cytokine leading to the production of IL-8 by many cells
  • neutralization of TNF- ⁇ appears earlier than IL-8 in the inflammatory cascade, it is unlikely that anti-TNF- would be effective as late as anti-IL-8 following acid- instillation.
  • Another factor that may contribute to the relatively wide therapeutic window of anti-IL-8 (at least 1 h) is that after its production, IL-8 must also diffuse to the endothelium and interact with neutrophils. Given the time necessary for IL-8 production and diffusion, it is conceivable that anti-IL-8 therapy given later than 1 h after acid aspiration would also be effective.
  • IL-8 is critical for the development of the acute injury following acid aspiration, it is likely that IL-8 mediates injury in conjunction with other proinflammatory molecules.
  • IL-8 appears to be a relatively weak neutrophil activator, although in vi tro studies indicate that it is an effective primer of activation by other mechanisms.
  • neutrophils were recruited without the appearance of wheal or flare.
  • neutrophils were recruited without releasing elastase or lysozyme.
  • IL-8 in acid aspiration lung injury, IL-8 is undoubtedly generated in conjunction with other cytokines, such as TNF- ⁇ and IL-1, and other inflammatory mediators, such as leukotrienes, complement fragments, and platelet activating factor.
  • cytokines such as TNF- ⁇ and IL-1
  • other inflammatory mediators such as leukotrienes, complement fragments, and platelet activating factor.
  • inhibition of IL-8 alone is capable of preventing the experimental lung injury generated by acid aspiration in rabbits.
  • Aspiration of gastric contents is a major clinical cause of morbidity and mortality and effective therapy for this condition is currently unavailable. Current management is limited to positive pressure ventilation and careful management of fluid therapy.
  • IL-8 is a distal cytokine
  • its neutralization may have more limited effects than neutralization of a more proximal, pluripotent cytokine, such as TNF- ⁇ .
  • neutralization therapy might be required only for a short time, during the time that IL-8 is generated.
  • IL-8 concentrations have returned towards normal in less than 12 hours.
  • alveolar fluid IL-8 concentrations in untreated rabbits were significantly lower than at 6 h, suggesting that a need for long-term anti-IL-8 therapy following a single acid aspiration might be unnecessary.
  • the time of onset of the aspiration would be known with certainty in many cases because gastric aspiration is frequently witnessed, whereas in other clinical conditions, such as sepsis, the time of onset is often difficult to identify.
  • the delay in onset of the acid-aspiration injury allows a clinically feasible therapeutic window of at least one hour.
  • a potential limitation of anti-IL-8 therapy is that, like any anti-inflammatory therapy, it might inhibit the host immunity and increase the risk of infection.

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Abstract

On traite une lésion pulmonaire induite par le syndrome de Mendelson en administrant au patient une substance de fixation de l'IL-8, telle qu'un anticorps anti-IL-8, à la suite dudit syndrome.
PCT/US1996/001150 1995-01-23 1996-01-23 Procedes pour le traitement d'une lesion pulmonaire aigue induite par le syndrome de mendelson WO1996022785A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP8523042A JPH10512278A (ja) 1995-01-23 1996-01-23 酸吸引誘発急性肺損傷の治療方法
AU47716/96A AU4771696A (en) 1995-01-23 1996-01-23 Methods for the treatment of acid aspiration-induced acute lung injury
EP96903731A EP0806962A4 (fr) 1995-01-23 1996-01-23 Procedes pour le traitement d'une lesion pulmonaire aigue induite par le syndrome de mendelson

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US37707795A 1995-01-23 1995-01-23
US08/377,077 1995-01-23
US45404295A 1995-05-30 1995-05-30
US08/454,042 1995-05-30

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049426A1 (fr) * 1996-06-26 1997-12-31 Chugai Seiyaku Kabushiki Kaisha Medicaments destines aux lesions pulmonaires aigues dues a des causes indirectes, contenant un anticorps anti-il-8 comme principe actif
US6458355B1 (en) 1998-01-22 2002-10-01 Genentech, Inc. Methods of treating inflammatory disease with anti-IL-8 antibody fragment-polymer conjugates
US6468532B1 (en) 1998-01-22 2002-10-22 Genentech, Inc. Methods of treating inflammatory diseases with anti-IL-8 antibody fragment-polymer conjugates
US6870033B1 (en) 1997-02-21 2005-03-22 Genentech, Inc. Antibody fragment-polymer conjugates and humanized anti-IL-8 monoclonal antibodies
US7214776B2 (en) 1999-01-21 2007-05-08 Genentech, Inc. Antibody fragment-polymer conjugates and uses of same
US7282568B2 (en) 2002-12-16 2007-10-16 Medarex, Inc. Human monoclonal antibodies against interleukin 8 (IL-8)
WO2019140150A1 (fr) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Polythérapie faisant intervenir des anticorps anti-il-8 et des anticorps anti-pd-1 pour le traitement du cancer
WO2023192478A1 (fr) 2022-04-01 2023-10-05 Bristol-Myers Squibb Company Polythérapie avec des anticorps anti-il-8 et des anticorps anti-pd-1 pour le traitement du cancer

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANN. SURG., October 1990, Vol. 212, GOLDMAN et al., "Tumor Necrosis Factor-alpha Mediates Acid Aspiration-induced Systemic Organ Injury", pages 513-520. *
NATURE, 14 October 1993, Vol. 365, SEKIDO et al., "Prevention of Lung Reperfusion Injury in Rabbits by a Monoclonal Antibody Against Interleukin-8", pages 654-657. *
See also references of EP0806962A4 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049426A1 (fr) * 1996-06-26 1997-12-31 Chugai Seiyaku Kabushiki Kaisha Medicaments destines aux lesions pulmonaires aigues dues a des causes indirectes, contenant un anticorps anti-il-8 comme principe actif
AU709108B2 (en) * 1996-06-26 1999-08-19 Chugai Seiyaku Kabushiki Kaisha Therapeutic agent for acute lung injury resulting from indirect causes comprising anti-IL-8 antibody as active ingredient
US6870033B1 (en) 1997-02-21 2005-03-22 Genentech, Inc. Antibody fragment-polymer conjugates and humanized anti-IL-8 monoclonal antibodies
US6458355B1 (en) 1998-01-22 2002-10-01 Genentech, Inc. Methods of treating inflammatory disease with anti-IL-8 antibody fragment-polymer conjugates
US6468532B1 (en) 1998-01-22 2002-10-22 Genentech, Inc. Methods of treating inflammatory diseases with anti-IL-8 antibody fragment-polymer conjugates
US7214776B2 (en) 1999-01-21 2007-05-08 Genentech, Inc. Antibody fragment-polymer conjugates and uses of same
US8652468B2 (en) 1999-01-21 2014-02-18 Genentech, Inc. Methods of binding TNF-α using anti-TNF-α antibody fragment-polymer conjugates
US7507405B2 (en) 1999-01-21 2009-03-24 Genentech, Inc. Antibody fragment-polymer conjugates and uses of same
US8147830B2 (en) 1999-01-21 2012-04-03 Genentech, Inc. Antibody fragment-polymer conjugates and uses of same
US7842789B2 (en) 1999-01-21 2010-11-30 Genentech, Inc. Antibody fragment-polymer conjugates and uses of same
US8105588B2 (en) 2002-12-16 2012-01-31 Genmab A/S Human monoclonal antibodies against interleukin 8 (IL-8)
US7622559B2 (en) 2002-12-16 2009-11-24 Genmab A/S Human monoclonal antibodies against interleukin 8 (IL-8)
US8603469B2 (en) 2002-12-16 2013-12-10 Genmab A/S Methods of treating cancer with human monoclonal antibodies against interleukin 8
US7282568B2 (en) 2002-12-16 2007-10-16 Medarex, Inc. Human monoclonal antibodies against interleukin 8 (IL-8)
US10066012B2 (en) 2002-12-16 2018-09-04 Cormorant Pharmaceuticals Ab Human monoclonal antibodies against interleukin 8 (IL-8)
US10253093B2 (en) 2002-12-16 2019-04-09 Cormorant Pharmaceuticals Ab Human monoclonal antibodies against interleukin 8 (IL-8)
US11339215B2 (en) 2002-12-16 2022-05-24 Cormorant Pharmaceuticals Ab Methods of treating cancer with human monoclonal antibodies against interleukin 8 (IL-8)
WO2019140150A1 (fr) 2018-01-12 2019-07-18 Bristol-Myers Squibb Company Polythérapie faisant intervenir des anticorps anti-il-8 et des anticorps anti-pd-1 pour le traitement du cancer
US11572405B2 (en) 2018-01-12 2023-02-07 Bristol-Myers Squibb Company Combination therapy with anti-IL-8 antibodies and anti-PD-1 antibodies for treating cancer
WO2023192478A1 (fr) 2022-04-01 2023-10-05 Bristol-Myers Squibb Company Polythérapie avec des anticorps anti-il-8 et des anticorps anti-pd-1 pour le traitement du cancer

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JPH10512278A (ja) 1998-11-24
EP0806962A1 (fr) 1997-11-19
EP0806962A4 (fr) 2001-01-10
CA2211115A1 (fr) 1996-08-01

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