WO2023242440A1 - Traitement des poumons chez les nourrissons - Google Patents

Traitement des poumons chez les nourrissons Download PDF

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WO2023242440A1
WO2023242440A1 PCT/EP2023/066470 EP2023066470W WO2023242440A1 WO 2023242440 A1 WO2023242440 A1 WO 2023242440A1 EP 2023066470 W EP2023066470 W EP 2023066470W WO 2023242440 A1 WO2023242440 A1 WO 2023242440A1
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composition
use according
igf
preterm
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Norman Barton
Kurt ALBERTINE
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Oak Hill Bio Limited
University Of Utah Research Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1754—Insulin-like growth factor binding proteins
    • 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

Definitions

  • Bronchopulmonary dysplasia is a chronic respiratory disease that most often occurs in low-weight or premature infants who have received supplemental oxygen or have spent long periods of time on a breathing machine (mechanical ventilation), such as infants who have acute respiratory distress syndrome. BPD can also occur in older infants who experience abnormal lung development or some infants that have had an infection before birth (antenatal infection) or placental abnormalities (such as preeclampsia). Antenatal steroid treatment prior to preterm birth and early treatment with surfactant have reduced the need for high levels of respiratory support after birth.
  • Affected infants may have rapid, laboured breathing and bluish discoloration of the skin due to low levels of oxygen in the blood (cyanosis). Infants are not born with BPD, the condition results from damage to the lungs
  • the under-developed lung can lead to an inability to oxygenate tissue, which can be described clinical as acute respiratoiy distressed syndrome (ARDS), a life-threating conditions where the lungs cannot provide the bodies vital organs with enough oxygen. This is about respiratory gas exchange and is an acute syndrome as opposed to long term damage and chronic illness.
  • ARDS acute respiratoiy distressed syndrome
  • the present inventors have established maturation and differentiation of lung tissue can stimulated by generating therapeutic levels of IGF-1 rapidly after birth. This leads to significant improvements in lung structure elaboration.
  • the present invention provides method of stimulating maturation of the lungs, to provide more structure.
  • the present inventors have also established that treating preterm infants with a complex of IGF-1 and an IGF binding protein (such as IGFBP-3) increases the levels of caspase-3 in the lungs. This in turn leads to increased apoptosis and gas exchange.
  • this complex is administered in the first few days after birth and in combination with positive airway pressure and/or mechanical ventilation the infants breathing is significantly stabilised and incidences of respiratory distress syndrome are reduced.
  • a lower respiratory severity score (a measure of the difficult "breathing”
  • A-a alveolar-arterial gradientf which measures the difference between the oxygen concentration in the alveoli and arterial system
  • better diffusion for example a lower barrier to diffusion
  • P/F ratio or a proxy thereof, such as S/F ratio
  • reduced lung stiffness and/or reduced oxygenation index (which may be a marker for neonatal outcomes including mortality).
  • the present disclosure relates to treatment of the sickest patient population, namely those receiving positive airway pressure and/or mechanical ventilation, in particular mechanical ventilation
  • a method for stimulation of maturation and/or differentiation of lung tissue in a preterm infant by administering a therapeutic amount of a composition comprising IGF-1 and an IGF binding protein (such as IGFBP-3) for example as a complex, such as parenteral administration.
  • a composition comprising IGF-1 and an IGF binding protein (such as IGFBP-3) for example as a complex, such as parenteral administration.
  • IB A composition comprising IGF-1 and an IGF binding protein (such as IGFBP-3), for example as complex, for use in the manufacture of a medicamentfor the stimulation of maturation and/or differentiation of lung tissue in a preterm infant, for example parenteral administration.
  • IGFBP-3 IGF binding protein
  • treated patients for example neonates
  • treated patients have a larger airspace epithelial cells in comparison to untreated patients.
  • a method or composition for use according to any preceding paragraph wherein treated patients (for example neonates) have higher oxygen saturation levels than untreated patients, for example as measured by pulse oximetry. 16. A method or composition for use according to any preceding paragraph, wherein the treated patients (for example neonates) have lower peak inspiratoiy pressure than untreated patients.
  • the treated preterm infant has a fractional inspired oxygen level that is lower than untreated preterm infants (or an average thereof), for example 0.21, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9 or 0.95, in particular in the first 36 hours of life.
  • preterm infant is 23 to 34 weeks post gestation, when treatment is initiated, for example 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 or 34 weeks.
  • blood pressure such as mean system blood pressure
  • diastolic pressure is stabilised, for example in the range 60 to 90mmHg, for example 60, 65, 70, 75, 80, 85, 90mmHg or such as where the diastolic pressure is higher than an untreated preterm infant (in particular in the period up to 72 hours post birth).
  • systolic pressure is stabilised, for example is higher than untreated preterm infants (in particular in the period up to 72 hours post birth), such as stabilised in the range 30 to 60mmHg, in particular 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60mmHg.
  • a method or composition for use according to paragraph 36, wherein more robust is a lower heart rate in comparison to untreated preterm infants (or average thereof), for example a bpm in the range about 120 to 180, such as 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175 or 180 bpm.
  • composition comprises equimolar amounts of IGF-1 and IGFBP-3.
  • composition for use according to any preceding paragraphs, wherein the composition is administered by infusion, for example by continuous infusion.
  • composition for use according to any preceding paragraph, wherein the composition is administered subcutaneously, for example as a depot injection, such as once, twice or three times a day.
  • a method or composition for use according to any preceding paragraph wherein the complex is used in a combination therapy for example in combination with therapies normally employed in preterm infants and neonates, such as surfactant replacement therapy.
  • the capillary surface density in the treated infants is improved, for example by at least 10%.
  • lung capillaries are increased.
  • lung epithelial surface is increased in treated infants, for example by 10, 15, 20, 25, 30, 35, 40, 45 or 50% or more.
  • a method of treatment or prophylaxis of acute respiratoiy failure and/or acute respiratory injury in a preterm comprising administering a therapeutic amount of a composition comprising IGF-1 and an IGF binding protein (such as IGFBP-3], for example as complex, such as 1:1 complex.
  • composition comprising IGF- 1 and an IGF binding protein (such as IGFBP-3], for example as complex for use in preventing or minimising multiple organ dysfunction syndrome, for example induced acute respiratory distress, for example in infants with an under developed lung, particular at the saccular stage.
  • IGFBP-3 IGF binding protein
  • composition comprising IGF- 1 and an IGF binding protein (such as IGFBP-3], for example as complex for use in treatment or prevention of acute lung injury, for example in infants with an under developed lung, particular at the saccular stage.
  • IGFBP-3 IGF binding protein
  • the oxygenation index is reduced in treated infants, for example 4 or less (in particular from day 3 of treatment or life], such as 2.5 or 2. This may also be considered evidence of improved robustness.
  • the P/F ratio is increased in treated infants, for example is at least 300 (including where averages are maintained at 300 or above], such as 350 (in particular from day 4 of treatment or life].
  • treated patients have improved structural thinning of saccular walls in comparison to untreated patients.
  • treated patients have a PCNA relative protein abundance that is numerically lower in comparison to untreated patients.
  • treated patients have higher oxygen saturation levels than untreated patients, for example as measured by pulse oximetry. In one embodimenttreated patients (neonates] have higher aortic pressure.
  • the IGF-1 composition is administered subcutaneously, for example as a depot injection, for example once, twice or three times each day.
  • the IGF-1 levels are raised to therapeutic levels by continuous infusion.
  • the IGF-1 levels are raised to therapeutic levels by continuous infusion and then the administration is changed to subcutaneous (once, twice or three times a day].
  • the present treatment is employed in a combination therapy, for example with other treatments usually employed in preterm infants, such as surfactant therapy.
  • Bronchopulmonary dysplasia refers to a form of chronic lung disease that typically affects preterm infants.
  • Preterm infants generally have under-developed lungs, which necessitates the use of mechanical ventilation.
  • mechanical ventilation Unfortunately, because their lungs are vulnerable, the high amounts of inhaled oxygen and pressure introduced by mechanical ventilation may overstretch the alveoli, resulting in inflammation and scarring to the tissues of the airway and alveoli. This in turn affects the proper development of the alveoli - fewer and larger alveoli develop compared to usual and the interstitium is thickened. This produces a vicious cycle where the infant is increasingly reliant on mechanical ventilation and is unable to wean from artificial ventilation.
  • New bronchopulmonaiy dysplasia refers to a form of BPD whereby there is less inflammation and scarring than in classic BPD.
  • new BPD there is abnormal lung development resulting in an under-developed or immature lung.
  • alveolar simplification that includes fewer secondary septa, reduced capillary growth, and smaller surface density for capillary endothelial cells and airspace epithelial cells.
  • Respiratoiy distress syndrome refers to a breathing disorder that in particular afflicts newborn babies, especially preterm infants (although it can also affect full-term infants].
  • the syndrome occurs when the lungs are not fully developed, as a result of which the lungs fail to manufacture sufficient amounts of surfactant
  • Surfactant is a fluid that helps to keep the alveoli open; a lack of surfactant causes the alveoli to collapse with each breath. This leads to cellular damage, resulting in the accumulation of damaged cells in the airway, which in turn makes breathing even more difficult
  • Acute respiratory distress syndrome includes acute onset of disease, chest radiograph demonstrating bilateral pulmonary infiltrates, lack of significant left ventricular dysfunction and Pao2/Fio2 (PF) ratio ⁇ 300 for ALI (acute lung injury) or ⁇ 200 for ARDS.
  • PF Pao2/Fio2
  • Hypoxemic respiratory failure happens when there is not enough oxygen transport into the blood (hypoxemia). Heart and lung conditions are the most common causes. Hypoxemic respiratory failure is also called hypoxic respiratory failure. Hypoxemic respiratoiy failure is associated with increased risk of mortality, morbidity, and worse neurological outcomes. Oxygenation index (01) is routinely used as an indicator of severity of HRF in neonates, with an arbitrary cutoff of 15 or less for mild HRF, between 16 and 25 for moderate HRF, between 26 and 40 for severe HRF, and more than 40 for veiy severe HRF.
  • Caspase-3 is a member of the cysteine-aspartic acid protease (caspase) family. Caspase-3 plays a central role in cellular apoptosis. It is activated by caspases-8, 9 and 10 and its role in turn is to cleave and activate caspases-6 and 7. Caspase-3 is typically referred to as an executioner caspase because of its role in co-ordinating the degradation of cytoskeletal proteins and the destruction of other cellular structures.
  • a corresponding infant as employed herein is an infant with corresponding parameters, for example gestational age, weight and the like, for example which is usually untreated.
  • Less or minimal intervention refers to the amount of support from a carer required by a treated infant being less. For example, when an infant’s breathing is stable then less adjustments have to be made to instruments to keep the respiratory gases with the predefined parameters. This is not about whether the infant requires a nasal canula (the least invasive support), continuous positive airway pressure (which helps keep the lungs inflated using a higher air pressure than a standard nasal canula); or mechanical ventilation. Instead, it is about the number of adjustments that have to be made to keep the breathing within a predefined "desirable" range.
  • synchronized intermittent mandatory ventilation with pressure- controlled, with warmed and humidified gas is employed.
  • F1O2 is set to attain target hemoglobin oxygen saturation of 90-94% (Path 60-90 mmHg, such as 60, 65, 70, 75, 80, 85, 90mmHg), for example by pulse oximetry (Model SurgiVet V9200IBP/Temp, Smith Medical ASD, Inc., St. Paul, MN).
  • peak inspiratory pressure is set to attain a target PaCC>2 between 45 and 60 mmHg (such as 45, 50, 55, 60), resulting in pH between 7.25-7.35 (such as 7.25. 7.26, 7.27, 7.28, 7.29, 7.30, 7.31, 7.32, 7.33, 7.34 or 7.35).
  • target expiratory tidal volume measured by the ventilator, in the range 5 to 7 mL/Kg, such as 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 or 7.
  • Fractional inspired oxygen as employed herein is an estimation of the oxygen content a person inhales and is thus involved in gas exchange at the alveolar level. Understanding oxygen delivery and interpreting Fi02 values are imperative for the proper treatment of patients with hypoxemia. It is the molar or volumetric fraction of oxygen in the inhaled gas.
  • oxygen-enriched air which means a higher- than-atmospheric F/O2.
  • Natural air includes 21% oxygen, which is equivalent to F/O2 of 0.21.
  • Oxygen-enriched air has a higher F/O2 than 0.21; up to 1.00 which means 100% oxygen.
  • F/O2 is typically maintained below 0.5 even with mechanical ventilation, to avoid oxygen toxicity, but there are applications when up to 100% is routinely used.
  • the abbreviated alveolar air equation is:
  • PAO 2 , P E 0 2 , and P1O2 are the partial pressures of oxygen in alveolar, expired, and inspired gas, respectively, and VD/Vtis the ratio of physiologic dead space over tidal volume.
  • a lower oxygenation index is better - this can be inferred by the equation itself. As the oxygenation of a person improves, they will be able to achieve a higher PaO2 at a lower Fi02. This would be reflected on the formula as a decrease in the numerator or an increase in the denominator - thus lowering the 01.
  • an 01 threshold is set for when a neonate should be placed on ECMO, for example >40.
  • PA02 representing alveolar oxygen pressure
  • PA02 (Patm - PH2O) Fi02 - PaCO2/RQ
  • Limitations of 01 include the need for an indwelling arterial catheter for frequent sampling and that it is an intermittent measurement of oxygenation status by nature.
  • P/F ratio is a powerful objective tool to identify acute hypoxemic respiratory failure at any time while the patient is receiving supplemental oxygen, a frequent problem faced by documentation specialists where no room air ABG (arterial blood gas] is available or pulse ox readings seem equivocal.
  • ABG arterial blood gas
  • A-a Gradient PA02 - Pa02.
  • PA02 (Patm - PH20] Fi02 - PaC02/RQ
  • a P/F Ratio less than 300 indicates acute respiratoiy failure.
  • P/F ratio ⁇ 250 is equivalent to a p02 ⁇ 50 mm Hg on room air
  • S/F ratio is a proxy for P/F ratio.
  • the arterial p02measured by arterial blood gas (ABG] is the definitive method for calculating the P/F ratio.
  • the SpO2 measured by pulse oximetry can be used to approximate the p02, as shown in the Table below. It is important to note that estimating the p02 from the SpO2 becomes unreliable when the SpO2 is 98% - 100%. Conversion of SpO2 to p02
  • FI02 derived from nasal cannula flow rates can then be used to calculate the P/F ratio.
  • hypoxemic is where oxygen levels in the blood are lower than normal.
  • Very preterm infants refers to 32 weeks or less gestation age, for example 31 weeks or less, 30 weeks or less. 29 weeks or less, 28 weeks or less, 27 weeks or less, 26 weeks or less, 25 weeks or less, 24 weeks or less, 23 weeks or less or 22 weeks.
  • the preterm infant is human.
  • the lowest weight (not necessarily the most premature) infants may benefit the most from the therapy of the present disclosure, for example infants lKg or less.
  • a low birthweight baby may be a baby with poor growth in the womb (intrauterine growth restriction-IUGR).
  • the treatment according to the present disclosure is employed in a low birth weight infant regardless of whether said infant is born prematurely.
  • Stabilising blood pressure as employed herein is a fit for purpose test, as the infant is able to urinate, preferably without intervention using a vasopressor and/or a diuretic.
  • the stabilised blood pressure stabilises one or more systemic functions in the infant.
  • stabilised blood pressure is stabilisation of mean systemic pressure.
  • the stabilisation minimises incidences of or prevents hypertension. In one embodiment the disclosure does not relate to hypertension.
  • stabilisation minimises or prevents hypotension, for example a mean systemic pressure below 30mgHg.
  • mean systemic pressure is in maintained in the range 30 to 60mgHg, for example 30, 35, 40, 45, 50, 55 or 60 mgHg.
  • the disclosure reduces the need for intervention, for example treatment with a vasopressor and/or diuretic.
  • Blood flow as employed herein refers to movement of blood in the infant When the blood flow is good and stabilised it reaches all the organs and tissues, for example infants are perfused and pink. This blood flow then supports the function of the different organs, such as the kidneys, lungs, stomach etc. Meaningful blood pressure readings may not be feasible in some infants, for example the amount of blood may so small that the pressure readings using instruments are anomalous. Nevertheless, these infants benefit from the treatment of the present disclosure. Thus, blood flow as employed herein is a fit for purpose test based one or more key biological functions - Is the infant urinating, perfused, breathing adequately etc, and preferably all of the same.
  • the disclosure is not for the treatment of bronchopulmonaiy dysplasia, as defined herein (i.e. traditional BPD).
  • a corresponding infant as employed herein is an infant with corresponding parameters, for example gestational age, weight and the like.
  • Less or minimal intervention as employed herein refers to the amount support from a career required by a treated infant being less. For example, when an infant’s breathing is stable then less adjustments have to be made to instruments to keep the respirator gases with the predefined parameters. This is not about whether the infant is a nasal canula (the least invasive support), continuous positive airway pressure (which helps keep the lungs inflated using a higher air pressure than a standard nasal canula); or mechanical ventilation. Instead, it is about the number of adjustments that have to be made to keep the breathing within a predefined "desirable" range.
  • synchronized intermittent mandatory ventilation with pressure- controlled, with warmed and humidified gas is employed.
  • F1O2 is set to attain target hemoglobin oxygen saturation of 90-94% (Path 60-90 mmHg) by pulse oximetry (Model SurgiVet V9200IBP/Temp, Smith Medical ASD, Inc., St Paul, MN).
  • peak inspiratory pressure is set to attain a target PaCC>2 between 45 and 60 mmHg, resulting in pH between 7.25-7.35.
  • target expiratory tidal volume measured by the ventilator, in the range 5 to 7 mL/Kg.
  • calculated oxygenation index (01) [(Paw x FjO2)/PaO2], P/F (PaO2/FjO2) ratio, and Alveolar-arterial (A-a) gradient [((F 0 /100) x (640-47))-(PaCO /0.8)-Pa0 ].
  • barometric pressure is about 640 mmHg.
  • the alveolar-arterial (A-a) gradient in a treated infant is improved over a corresponding untreated infant.
  • IGFBP-3 refers to insulin-like growth factor binding protein 3.
  • IGFBP-3 is a member of the insulin-like growth factor binding protein family.
  • IGFBP-3 may be from any species, including bovine, ovine, porcine and human, in native-sequence or variant form, including but not limited to naturally-occurring allelic variants, in particular human.
  • IGFBP-3 may be from any source, whether natural, synthetic or recombinant, provided that it will bind IGF-I at the appropriate sites. IGFBP-3 can be produced recombinantly, as described in PCT publication WO 95/04076.
  • the therapeutic composition may also contain other substances such as water, minerals, carriers such as proteins, and other excipients known to one skilled in the art.
  • the method or composition comprises 100 to 600 pg/Kg/24hours of the IGF-l/IGFBP-3 complex. In one embodiment, the method or composition comprises 200 to 500
  • Figure 3A-D shows (Group 2) physiological parameters for preterm lambs managed by invasive mechanical ventilation for 3d. Continuous iv infusion of rhIGF-l/rhIGFBP-3 (1.5 mg/Kg/day; blacks squares) led to somewhat better systemic hemodynamic and heart rate outcomes [Panels A-D ⁇ relative to vehicle-control preterm lambs (open circles); however, no statistically significant differences were detected.
  • FIG. 4A-B RhIGF-l/rhIGFBP-3 led to phosphoiylation of IGF-1 receptor (IGF-l-R) in sheep endothelial cells in vitro.
  • Panel A The response was concentration-dependent.
  • Panel B Only 50 ng/mL and 100 ng/mL rhIGFl/rhIGFBP-3 treatments led to IGF-1 level above background at all timepoints tested.
  • Control BSA, bovine serum albumin
  • Figure 5 Shows the respiratory severity score for 7 day lamb study.
  • Figure 6 Shows the A-a gradient for 7 day lamb study.
  • Figure 8 Shows the P/F ratio for 7 day lamb study.
  • Figure 9 Shows the S/F ratio for 7 day lamb study.
  • Figure 10A-D shows Group 2 alveolar capillary growth in preterm lambs managed by invasive mechanical ventilation for 3d. Immunohistochemistry was used to label capillary endothelial cells (brown color in [Panels A and B; the panels are the same magnification; see scale bar). Quantitative histology [Panels C and D) showed that continuous iv infusion of rhIGF-l/rhIGFBP-3 (1.5 mg/Kg/day; black squares) led to significantly greater capillary surface density (p ⁇ 0.1) and epithelial surface density (p ⁇ 0.1) compared to vehicle-control (white circles).
  • Figure 12A-C shows (Group 2) semi-quantitative normalized protein abundance by immunoblot in lung parenchyma in preterm lambs managed by invasive mechanical ventilation for 3d.
  • Continuous iv infusion of rhIGF-l/rhIGFBP-3 led to significantly greater abundance of cleaved caspase-3 [Panel B; p ⁇ 0.1) compared to the vehicle-control (white circles).
  • No statistical differences were detected for normalized protein abundance of proliferating cell nuclear antigen (PCNA; Panel A) or fetal liver kinase-1 (Flk-1 (VEGF-R2; Panel C).
  • Figure 13 Shows quantitative morphological results show that indices of alveolar formation are significantly better (* p ⁇ 0.05 by unpaired t-test) in rhIGF-l/rhIGFBP-3-treated preterm lambs compared to control preterm lambs, both groups of which were mechanically ventilated for 7 days.
  • rhIGF-l/rhIGFBP-3-treated preterm lambs maintained their weight, whereas vehicle-control preterm lambs lost weight from day of life 1 through day of life 3 (p ⁇ 0.1).
  • rhIGF-l/rhIGFBP-3 infusion did not adversely affect the liver and kidneys of the preterm lambs.
  • the data shows that 3 days of continuous iv infusion of rhlGF- l/rhIGFBP-3 improved some pulmonary and cardiovascular outcomes, without toxicity, in mechanically ventilated preterm lambs.
  • Protocols adhered to APS/NIH guidelines for humane use of animals for research and were prospectively approved by the IACUC at the University of Utah Health Sciences Center.
  • Plasma levels of IGF-1 protein were measured by endpoint ELISA, using a human IGF-1 ELISA kit (Mediagnost; Reutlinger, Germany), the reagents for which cross-react with IGF-1 from many species, including sheep. Plasma samples were acid-dissociated from binding proteins prior to analysis of free IGF-1. IGF-1 levels were extrapolated from a standard curve derived from recombinant human IGF-1.
  • Term newborn lambs (about 24h old) were anesthetized (ketamine; 10 mg/Kg, im; isoflurane ⁇ 2.5%, inhaled) and intubated for insertion of catheters into a common carotid artery and external jugular vein for plasma sampling, which was done after the term lambs recovered from anesthesia ( ⁇ 48h of life).
  • rhIGF-l/rhIGFBP-3 led to downstream signaling by sheep vascular endothelial cells (ATCC- Manassas, VA).
  • ATCC- Manassas, VA sheep vascular endothelial cells
  • Cells were seeded at60,000/well in a 96- well tissue culture plate. The next day, cells were washed once and left overnight in serum-free Dulbecco's Modified Eagle Medium (Invitrogen-City, state). After serum starvation, the cells were treated with 0, 10, 50, or 100 ng/mL human IGF1 (R&D systems) or bovine serum albumin (Fisher Scientific-city state) for 5, 10, or 30 min.
  • Cells were washed and then lysed on ice for 30 min in 100 pL lysis buffer (10 mM HEPES (4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid), 0.5% Triton-x 100), with halt protease and phosphatase inhibitor cocktail (Fisher Scientific).
  • Cell lysates were analyzed for pIGF- 1R, according to manufacturer’s instructions, using AlphaLISA SureFire Ultra kit (Perkin Elmer catalog #ALSU-PLGFR-A500). Briefly, 10 pL of cell lysate and 5 pL acceptor mix were added to a PerkinElmer white half area plate and incubated for lh in the dark at room temperature. Five pL of donor mix was added and incubated in the dark for lh at room temperature. The plate was read on an Envision instrument.
  • a pilot dosage-finding pharmacokinetic study of continuously infused rhIGF-l/rhIGFBP-3 was done to define the optimal dosage required to achieve a plasma concentration of ⁇ 125 ng/mL during MV for 3d. Continuous infusion was employed because it was determined that IGF-1 has a ti/2 in plasma of ⁇ 2h in lambs.
  • the tested dosage range of 0.5, 1.5, or 4.5 mg/Kg/d bracketed the physiological range of plasma IGF-1 levels in normal fetal and term lambs determined from the first study. Two preterm lambs were treated with each dosage. Once the optimal dosage was identified (1.5 mg/Kg/d), four more preterm lambs were studied with this dose (n 6).
  • Preterm lambs were resuscitated through the endotracheal tube, using a programmed resuscitation box.
  • the lambs were weighed, placed prone on a veterinary sling atop a radiantly heated NICU bed, and connected to a Drager ventilator (model VN500, Lubeck, Germany). Sedation was the same for all ventilated preterm lambs (pentobarbital as needed and buprenorphine every 6h).
  • Lambs were supported with synchronized intermittent mandatory ventilation that was pressure-controlled, with warmed and humidified gas.
  • F1O2 was adjusted to attain target hemoglobin oxygen saturation of 90-94% (Path 60-90 mmHg) by pulse oximetry (Model SurgiVet V9200IBP/Temp, Smith Medical ASD, Inc., St. Paul, MN). Peak inspiratory pressure was adjusted to attain a target PaCCh between 45 and 60 mmHg, resulting in pH between 7.25-7.35. Target expiratory tidal volume, measured by the ventilator, was 5 to 7 mL/Kg.
  • Orogastric feeding of ewe’s colostrum (Kid & Lamb Colostrum Replacement, Land 0 Lakes, Arden Hills, MN) was started at ⁇ 3h of postnatal life (3 mL) and the volume was gradually increased as tolerated, with target over the first week of postnatal life of ⁇ 60 kcal/Kg/d.
  • Parenteral dextrose was infused to maintain plasma glucose between 60 and 90 mg/dL.
  • Arterial blood and urine samples were collected every 24h to measure plasma levels of IGF-1 protein, as well as indicators of liver and kidney injuiy (analyzed at Associated Regional and University Pathologists (ARUP) Laboratories, Salt Lake City), respectively.
  • Paraffin-embedded tissue blocks were prepared for histology and quantitative histology, including quantitative immunohistochemistry to assess structural indices of alveolar formation and alveolar capillaiy growth.
  • the right caudal lobe of the lung was used for molecular analyses (snap- frozen in liquid nitrogen and stored at -80°C). We used systematic, uniform, and random, protocols for unbiased sampling of lung tissue.
  • Physiological variables and quantitative histology results are summarized as mean ⁇ standard deviation (standard deviation, SD) or mean (interquartile range, IQR), as shown in the tables and figures.
  • IGF-1 protein level plateaued at ⁇ 140 ng/mL for the last 24h of the 3d study period (p ⁇ 0.05 compared to this set’s pretreatment baseline level).
  • plasma IGF-1 protein level significantly decreased from the set’s baseline level (91 ⁇ 40 ng/mL) to a nadir of ⁇ 30 ng/mL for the last 48h of the 3d study period (36 ⁇ 25 ng/mL at 60 and 72h; p ⁇ 0.05).
  • FIG. 11 Histological examples of alveolar capillary endothelial cell identification by immunohistochemistry are shown in Figure 11 and was performed using immunostained sections of lung tissue to quantify indices of alveolar capillary growth and counterstain to identify epithelial cells.
  • Stereological assessment of surface density detected statistically significantly larger surface density for capillary endothelial cells and airspace epithelial cells for the rhIGF-1/rhIGFBP- 3- group compared to the vehicle-control preterm lambs (p ⁇ 0.1) (see Figures 11C and D).
  • Protein abundance in lung parenchyma was assessed semi-quantitatively and shown in Figure 12. Statistical difference was detected for cleaved caspase 3, for which the relative protein abundance was significantly greater for the rhIGF-l/rhIGFBP-3-treated preterm lambs compared to the vehicle control preterm lambs (p ⁇ 0.1). Otherwise, no statistical differences were detected for protein abundance of proliferating cell nuclear antigen or fetal liver kinase- 1 (Flk-1) between the two groups.
  • Physiological parameters for respiratory gas exchange are presented in Figure 2. Results are shown for 12h epochs of postnatal age during the 3d of MV. Targets were SaCh range 90-94% (Path range 60-90 mmHg) for oxygenation and PaCCh range 45-60 mmHg for ventilation. Although numerical results favored rhIGF-l/rhIGFBP-3 treatment, no statistical differences were detected between the rhIGF-l/rhIGFBP-3-treated versus vehicle-control preterm lambs for the applied FiC>2 or PIP to sustain the oxygenation and ventilation targets, respectively (Figures 2A-D). OI and A-a gradient were significantly improved in rhIGF-l/rhIFGBP-3 treated lambs (Table 2).
  • Fluid balance parameters are summarized in Table 4. Average results are reported for 12h epochs. No statistical differences were detected for intravenous infusion of saline or dextrose, total fluid intake, enteral milk intake, or urine output between the rhIGF-l/rhIGFBP-3- treated versus vehicle-control preterm lambs.
  • Liver function and renal function test values are summarized in Tables 5 and 6, respectively. Plasma samples were taken while fetal lambs had their umbilical cord intact (‘pre’ in Table 5), and at'24h’ and ‘72h’. Liver function was assessed by measurement of plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), total bilirubin, and direct bilirubin. Indicators of kidney function were urine output, creatinine, blood urea nitrogen, lactate, and urine microalbumin. No differences were detected between the rhIGF-l/rhIGFBP-3-treated versus the vehicle-control preterm lambs. The levels were within reference limits for fetal lambs, adult sheep, and adult humans (Tables 5 and 6).
  • IGF-1 signaling while typically protective against apoptosis, also is proapoptotic. Perhaps in the context of the immature lung stressed by preterm birth and MV with oxygen-rich gas, etc., IGF-1 signaling may shift the balance of apoptosis versus proliferation among cells in the lung.
  • Preterm lambs ( ⁇ 128d gestation; saccular stage lung development) were divided into two groups, both of which were mechanically ventilated for 7d.

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Abstract

Un procédé de stimulation de la maturation et/ou de la différenciation de tissu pulmonaire chez un nourrisson prématuré et/ou un procédé de traitement ou de prophylaxie du syndrome de détresse respiratoire chez un nourrisson prématuré (également appelé ici nouveau-né), un bébé de faible poids à la naissance, un nourrisson atteint d'une maladie de membrane hyaline ou d'une maladie de déficience en tensioactif par administration d'une quantité thérapeutique d'une composition comprenant IGF-1 et une protéine de liaison à l'IGF (telle que IGFBP-3) par exemple en tant que complexe, en combinaison avec une pression des voies respiratoires positive et/ou une ventilation mécanique et un procédé de stimulation de la maturation et/ou de la différenciation du tissu pulmonaire chez un nourrisson prématuré,].
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