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Pilot dose-ranging of rhIGF-1/rhIGFBP-3 in a preterm lamb model of evolving bronchopulmonary dysplasia

Pediatric Research volume 93, pages 1528–1538 (2023)Cite this article

Abstract

Background

Low levels of insulin-like growth factor-1 (IGF-1) protein in preterm human infants are associated with bronchopulmonary dysplasia (BPD). We used our preterm lamb model of BPD to determine (1) dosage of recombinant human (rh) IGF-1 bound to binding protein-3 (IGFBP-3) to reach infant physiologic plasma levels; and (2) whether repletion of plasma IGF-1 improves pulmonary and cardiovascular outcomes.

Methods

Group 1: normal, unventilated lambs from 128 days gestation through postnatal age 5 months defined normal plasma levels of IGF-1. Group 2: continuous infusion of rhIGF-1/rhIGFBP-3 (0.5, 1.5, or 4.5 mg/kg/day; n = 2) for 3 days in mechanically ventilated (MV) preterm lambs determined that 1.5 mg/kg/day dosage attained physiologic plasma IGF-1 concentration of ~125 ng/mL, which was infused in four more MV preterm lambs.

Results

Group 1: plasma IGF-1 protein increased from ~75 ng/mL at 128 days gestation to ~220 ng/L at 5 months. Group 2: pilot study of the optimal dosage (1.5 mg/kg/day rhIGF-1/rhIGFBP-3) in six MV preterm lambs significantly improved some pulmonary and cardiovascular outcomes (p < 0.1) compared to six MV preterm controls. RhIGF-1/rhIGFBP-3 was not toxic to the liver, kidneys, or lungs.

Conclusions

Three days of continuous iv infusion of rhIGF-1/rhIGFBP-3 at 1.5 mg/kg/day improved some pulmonary and cardiovascular outcomes without toxicity.

Impact

  • Preterm birth is associated with rapid decreases in serum or plasma IGF-1 protein level. This decline adversely impacts the growth and development of the lung and cardiovascular system. For this pilot study, continuous infusion of optimal dosage of rhIGF-1/rhIGFBP-3 (1.5 mg/kg/day) to maintain physiologic plasma IGF-1 level of ~125 ng/mL during mechanical ventilation for 3 days statistically improved some structural and biochemical outcomes related to the alveolar formation that would favor improved gas exchange compared to vehicle-control. We conclude that 3 days of continuous iv infusion of rhIGF-1/rhIGFBP-3 improved some physiological, morphological, and biochemical outcomes, without toxicity, in mechanically ventilated preterm lambs.

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Fig. 1: Group 1 was plasma level of IGF-1 protein in normal, unventilated fetal and postnatal lambs.
Fig. 2: RhIGF-1 led to phosphorylation of IGF-1 receptor (IGF-1-R) in sheep endothelial cells in vitro.
Fig. 3: Group 2 physiological parameters for preterm lambs managed by invasive mechanical ventilation for 3 days.
Fig. 4: Group 2 alveolar formation in preterm lambs managed by invasive mechanical ventilation for 3 days.
Fig. 5: Group 2 alveolar capillary growth in preterm lambs managed by invasive mechanical ventilation for 3 days.
Fig. 6: Group 2 semi-quantitative normalized protein abundance by immunoblot in lung parenchyma in preterm lambs managed by invasive mechanical ventilation for 3 days.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the dozens of undergraduate students and medical students who learned and provided neonatal intensive care to the preterm lambs. We also thank Angela Presson, PhD, MS, at the University of Utah for guidance for the study’s pilot design and statistical analysis, as well as Jennifer Bosco, PhD, and Bettina Stack-Logue, PhD, at Takeda Pharmaceutical Company who provided in vitro pharmacology support to characterize the effect of rhIGF-1 on sheep IGF-1 receptors.

Funding

Supported by research grant awards from Takeda (formerly Shire) Pharmaceuticals and NIH R01 HL110002 (K.H.A.) and T35 HL007744 (supported C.M.), and the Division of Neonatology, Department of Pediatrics, University of Utah.

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Authors and Affiliations

  1. Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA

    Kurt H. Albertine, Mar Janna Dahl, Andrew Rebentisch, Elaine Dawson, Akbar Nabi, Sydney Bowen, Cindy Miers, Zhengming Wang, Haixia Yang, Baifeng Yu & Robert Ward

  2. Division of Neonatology, Department of Pediatrics, University of California, Davis, Sacramento, CA, USA

    Donald M. Null

  3. Takeda Pharmaceutical Company Limited, Cambridge, MA, USA

    Dennis Keefe, J.-K. Chung, Z. Zhou, Norman Barton & Galen Carey

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Contributions

K.H.A.: Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. M.J.D.: Substantial contributions to acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. A.R.: Substantial contributions to acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. E.D.: Substantial contributions to acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. A.N.: Substantial contributions to acquisition of data, or analysis and interpretation of data; and final approval of the version to be published. S.B.: Substantial contributions to acquisition of data, or analysis and interpretation of data; and final approval of the version to be published. C.M.: Substantial contributions to acquisition of data, or analysis and interpretation of data; and final approval of the version to be published. Z.W.: Substantial contributions to acquisition of data, or analysis and interpretation of data; and final approval of the version to be published. H.Y.: Substantial contributions to acquisition of data, or analysis and interpretation of data; and final approval of the version to be published. B.Y.: Substantial contributions to acquisition of data, or analysis and interpretation of data; and final approval of the version to be published. D.M.N.: Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. D.K.: Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. J.-K.C.: Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. Z.Z: Substantial contributions to acquisition of data, or analysis and interpretation of data; and final approval of the version to be published. N.B.: Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. G.C.: Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published. R.W.: Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; drafting the article or revising it critically for important intellectual content; and final approval of the version to be published.

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Correspondence to Kurt H. Albertine.

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Competing interests

A competing interest is identified because the study was funded by an independent research grant award from Takeda Pharmaceuticals to the University of Utah for this study to be done in Dr Albertine’s lamb intensive care unit.

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Albertine, K.H., Dahl, M.J., Rebentisch, A. et al. Pilot dose-ranging of rhIGF-1/rhIGFBP-3 in a preterm lamb model of evolving bronchopulmonary dysplasia. Pediatr Res 93, 1528–1538 (2023). https://doi.org/10.1038/s41390-022-02272-9

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