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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2098-2103
Copyright © 1999 by The Endocrine Society

From the Clinical Research Centers

Growth Hormone (GH) Receptor Blockade with a PEG-Modified GH (B2036-PEG) Lowers Serum Insulin-Like Growth Factor-I but Does Not Acutely Stimulate Serum GH1

Michael O. Thorner, Christian J. Strasburger, Zida Wu, Martin Straume, Martin Bidlingmaier, Suzan S. Pezzoli, Kenneth Zib, John C. Scarlett and William F. Bennett

Division of Endocrinology and Metabolism (M.O.T., M.S., S.S.P.), Department of Medicine, and National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; Med Klinik Innenstadt (C.S., Z.W., M.B.), Ludwig-Maximilians University, 80336 Munich, Germany; and Sensus Corporation (K.Z., J.C.S., W.F.B.), Austin, Texas 78701

Address all correspondence and requests for reprints to: Dr. Michael O. Thorner, Department of Medicine, Box 466, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: mot{at}virginia.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
B2036-PEG, a GH receptor (GH-R) antagonist, is an analog of GH that is PEG-modified to prolong its action. Nine mutations alter the binding properties of this molecule, preventing GH-R dimerization and GH action. A potential therapeutic role of B2036-PEG is to block GH action, e.g. in refractory acromegaly. A phase I, placebo-controlled, single rising-dose study was performed in 36 normal young men (ages, 18–37 yr; within 15% ideal body weight). Four groups received a single sc injection of either placebo (n = 3 in each group, total n = 12) or B2036-PEG (0.03, 0.1, 0.3, or 1.0 mg/kg; n = 6 each dose). B2036-PEG and GH concentrations were measured 0, 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, and 144 h after dosing. Serum insulin-like growth factor-I was measured before and 1–7 days after dosing. All doses were well tolerated, with no serious or severe adverse reactions. B2036-PEG, at 1.0 mg/kg, reduced insulin-like growth factor-I by 49 ± 6% on day 5 (P < 0.001 vs. placebo). GH was measured by two independent methods: 1) modified Nichols chemiluminescence assay (empirically corrected for B2036-PEG cross-reactivity); and 2) direct GH two-site immunoassay, using monoclonal antibodies that did not react with B2036-PEG. There was good agreement between the two methods. GH did not change substantially at any B2036-PEG dose, suggesting that B2036-PEG does not interact with hypothalamic GH-Rs to block short-loop feedback. B2036-PEG may thus block peripheral GH action without enhancing its secretion.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE PRIMARY regulators of GH synthesis and secretion are the hypothalamic hormones GHRH and SRIF. Modulation of GH secretion occurs through negative feedback effects of both circulating GH and insulin-like growth factor-I (IGF-I) (1, 2, 3, 4). GH increases hypothalamic SRIF release, thus decreasing additional GH secretion by the pituitary (2). IGF-I inhibits somatotroph GH secretion, again resulting in a decrease in pituitary GH secretion (5). The relative importance (dominance) of GH and IGF-I in modulating GH release in normal man is not known. The development of a specific GH receptor (GH-R) antagonist (B2036-PEG) now makes it possible to determine the precise in vivo role of GH in modulating its own release. Use of this GH-R antagonist now provides a robust probe to unravel the complex nature of GH secretion. The GH-R antagonist, B2036-PEG, is a polypeptide hormone of recombinant DNA origin that is an analog of GH with nine mutations (6). These mutations alter the binding properties of the GH-R with this GH analog at site 1, where affinity is increased; and at site 2, where binding is abolished. Receptor dimerization is prevented and, thus, GH action is inhibited. Additionally, the B2036 protein is chemically modified (7) by covalently binding 4–5 polyethylene glycol polymers per molecule. PEG-modification (8) lengthens the biological half-life of the molecule by increasing the hydrodynamic volume, thus reducing the renal clearance (8). PEG-modification also reduces the likelihood of antibody formation, presumably by interfering with immune system recognition (9). Two PEG-modified proteins, PEG-L-asparaginase and PEG-adenosine deaminase, are currently approved and marketed in the United States.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Thirty-six healthy young men [mean (± SD) age, 25 ± 5 yr; range, 18–37 yr] who were within 15% of ideal body weight were studied, after giving written informed consent. The studies were carried out in accordance with the declaration of Helsinki (as amended in Hong Kong, 1989) and in compliance with current regulations. The studies were conducted by Pharma Bio-Research International B.V. (Zuidlaren, The Netherlands). In addition to safety assessment, the studies were designed to determine the effect of placebo and the GH-R antagonist B2036-PEG on IGF-I and GH release. After an overnight fast, placebo (n = 12) or B2036-PEG at doses of 0.03, 0.1, 0.3, or 1.0 mg/kg (n = 6 each dose) were administered between 0700 and 1000 h, as a single sc dose in a single-blind fashion, with escalation of the dose by group. Subjects were admitted to a research unit 41 h before test substance administration and were observed as inpatients until discharge on day 8, with outpatient visits on days 10, 21, 60, and 90. Samples for measurement of serum GH and B2036-PEG were drawn before and 0.25, 0.5, 1, 3, 6, 9, 12, 24, 36, 48, 72, 96, 120, and 144 h after test administration. Samples for IGF-I measurement were drawn before and 1–7 days after administration.

Assays and data analyses

GH antagonist (B2036-PEG) assay. The B2036-PEG RIA was based on competitive protein binding by competition of B2036-PEG with a trace amount of radiolabeled B2036-PEG (125I-B2036-PEG). The antibody was raised in rabbits, and the separation of bound and free antigen was achieved with a second antibody technique. The assays were performed commercially by Phoenix International Life Sciences, Inc. (Quebec, Canada). Assay sensitivity is 4.8 µg/L, with a range of 4.8–300 µg/L. The interassay coefficients of variation (CVs) were 1.6% at 87 µg/L and 4.5% at 199 µg/L. The intraassay CVs were 2.8% at 87 µg/L and 3.2% at 199 µg/L.

IGF-I assay. Total serum IGF-I was measured by RIA after acid-ethanol extraction, using a commercially available kit (Nichols Institute Diagnostics, San Juan Capistrano, CA). The assays were performed by Endocrine Sciences, Inc. Laboratories (Calabasas Hills, CA). The intraassay CV was 4.4% at 248 µg/L, and the interassay CV was 8.1% at 231 µg/L. There was no interference of B2036-PEG in the assay when a serum sample containing an IGF-I concentration of 200 µg/L was spiked with B2036-PEG concentrations of 700; 8,250; and 90,900 µg/L.

GH assay (performed at the University of Virginia). Serum GH concentrations were measured in duplicate with the Nichols LumaTag human GH (hGH) chemiluminescence assay (Nichols Institute Diagnostics). The protocol was modified as previously described (10). The sensitivity of the assay is 0.002 µg/L. The interassay CVs were 7.2% at 1.7 µg/L and 7.2% at 4.2 µg/L. The intraassay CVs were 4.9% at 0.2 µg/L, 6.7% at 2 µg/L, and 6.4% at 4.9 µg/L.

Cross-reactivity of B2036-PEG in GH chemiluminescence assay (University of Virginia). B2036-PEG cross-reactivity in the GH chemiluminescence assay was empirically assessed by assaying known concentrations of B2036-PEG (over a range from 0.5–107 µg/L) and quantifying in terms of GH-equivalent assay responses. Base-10 logarithmic GH-equivalent responses were nonlinear least squares regressed to base-10 logarithmic known B2036-PEG concentrations, in terms of an eighth-order polynomial (Fig. 1Go), and were used as an empirical correction to GH concentrations measured in the presence of known B2036-PEG concentrations.



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  		Figure 1. Cross-reactivity of B2036-PEG in the GH chemiluminescence assay. The base-10 logarithmic assay response (in µg/L GH equivalents) is related via an eighth-order polynomial regression to the base-10 known B2036-PEG concentration (in µg/L).

 
Assay cross-reactivity was directly demonstrated by high-performance liquid chromatography (HPLC) experiments in which B2036-PEG and hGH were physically separated and subsequently assayed in the GH chemiluminescence assay. Pure samples of 4 µg each of B2036-PEG and hGH, labeled as 125I-B2036-PEG and 125I-hGH, were clearly separable by reverse-phase HPLC (Fig. 2Go, left panel). The hGH fraction (fraction no. 17) clearly corresponds to the signal generated in the GH chemiluminescence assay at the same fraction number (inset). Cross-reactivity in the GH chemiluminescence assay is evident in HPLC-separated B2036-PEG (fractions no. 13–14) and hGH (fractions no. 17–18) from a high-dose B2036-PEG sample (Fig. 2Go, right panel), whereas no cross-reactive signal is apparent from a placebo sample necessarily containing no B2036-PEG (fraction no. 18 only).



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  		Figure 2. Reverse-phase HPLC of 125I-hGH and 125I-B2036-PEG. Left panel, 125I-hGH and 125I-B2036-PEG were separated on reverse-phase HPLC, using a fluorocarbon-based BioSeries Poly F column (Mac-Mod Analytical, Chadds Ford, PA) using a gradient of acetonitrile in 0.1% TFA (45–70% acetonitrile at 1.0% per min). The two pure compounds (4 µg each) were readily resolvable, eluting from the column at 54% and 58% acetonitrile for B2036-PEG and hGH, respectively. The chemiluminescence assay profile for the hGH sample (inset) corresponds directly with that observed from the HPLC separation. Right panel, 50 µL samples of two human serum samples (one from a placebo control; the other from a high-dose, 1.0 mg/kg B2036-PEG administration) were separated by the same HPLC protocol, and the fractions were measured in the GH chemiluminescence assay. The peak at fractions no. 17–18 corresponds to hGH, whereas that at fractions no. 13–15 corresponds to B2036-PEG cross-reactivity.

 
GH assay (performed at the University of Munich). Subsequently, the same samples were measured in a two-site immunoassay that does not cross-react with B2036-PEG. Two monoclonal antibodies of a panel of 40 high-affinity human GH antibodies were selected because they exhibited no detectable cross-reactivity with B2036-PEG (Fig. 3Go, A and B). They were directed to receptor binding sites 1 and 2 (designated 8B11 and 6C1, respectively). The combination of these two monoclonal antibodies into a sandwich assay, using immobilized 8B11 and biotin labeled 6C1, was the basis of the assay and resulted in a linear dose-response relationship. The assay exhibited a lower detection limit of 0.02 µg/L GH, an upper end of the working range of 50 µg/L for 25 µL serum samples, and no cross-reaction with B2036-PEG up to a concentration of 50,000 µg/L (Fig. 3CGo). The interassay CVs were 4.1% at 4.0 µg/L and 3.8% at 20 µg/L. The intraassay CVs were 3.4% at 0.25 µg/L, 1.9% at 2.5 µg/L, and 4.5% at 25 µg/L.



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  		Figure 3. In competitive displacement experiments, neither monoclonal antibodies (mAb) 8B11 (A) nor mAb 6C1 (B) showed cross-reaction with B2036-PEG. Both antibodies were raised against recombinant hGH. Combination of both antibodies into a sandwich assay system (C) reveals no bias in serum samples of hGH concentrations of 0, 0.8, and 11 µg/L when spiked with B2036-PEG concentrations up to 50 mg/L. B, bound. Bo, bound in presence of zero concentration of hGH or B2036-PEG.

 
Comparison of GH results obtained by independent methods. Serum GH levels obtained by the indirect method (subtracting the cross-reactivity of B2036-PEG in the GH chemiluminescence assay of individual samples based upon previously determined B2036-PEG concentrations) were compared with the GH results from the direct two-site immunoassay (in which there is no cross-reaction with B2036-PEG). Linear regression analysis to directly compare the results from the two assay methods indicates that the indirect assay produced GH values 1.245 ± 0.028 (@95% confidence) times that of the direct assay with no systematic bias (i.e. the intercept is 0.018 ± 0.037), r2 = 0.87 (Fig. 4Go).



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  		Figure 4. Correspondence of the indirect GH chemiluminescence assay (University of Virginia) to that of the direct two-site GH immunoassay (University of Munich). Linear regression analysis of the untransformed, linear-linear assay results indicates that the indirect assay produces GH concentration estimates that are 1.245 ± 0.028 (@95% confidence) times that of the direct assay, and that no bias exists (i.e. the regression intercept is 0.018 ± 0.037), r2 = 0.87.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All doses of B2036-PEG were well tolerated, with no serious or severe adverse reactions. There were no clinically relevant alterations in vital signs, safety laboratory tests, physical examinations, continuous electrocardiographic monitoring or 24-h calcium excretion. Nine adverse events were considered to be possibly and one probably related to study medication (5 during active treatment and 4 during placebo treatment).

B2036-PEG was detected in plasma samples after all doses. Mean serum concentrations of B2036-PEG, in response to 0.03, 0.1, 0.3, and 1.0 mg/kg B2036-PEG, are shown in Fig. 5Go. These data clearly demonstrate a dose-dependent increase in B2036-PEG levels, with peak levels occurring about 36 h after dose administration. The 1.0 mg/kg B2036-PEG dose produced concentrations greater than 5000 µg/L, from 24–144 h after administration.



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  		Figure 5. Mean (± SE) serum B2036-PEG concentrations (µg/L), in response to four doses (n = 6 each dose) of B2036-PEG ({diamondsuit} 0.03 mg/kg, • 0.1 mg/kg, {blacksquare} 0.3 mg/kg, {blacktriangleup} 1.0 mg/kg). Each dose was administered as a single sc injection in normal young men.

 
Mean percentage changes, from baseline, in serum IGF-I concentrations are shown in Fig. 6Go. There was a dose-dependent suppression of serum IGF-I levels that reached statistical significance on day 3 after administration of 0.3 mg/kg B2036-PEG (28 ± 7%, P = 0.01 vs. placebo, by ANOVA). The most substantial B2036-PEG-dependent suppression of IGF-I was observed on day 5, in response to the highest dose of 1.0 mg/kg B2036-PEG, when levels were reduced by 49 ± 6% (P < 0.001 vs. placebo, by ANOVA).



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  		Figure 6. Mean (± SE) percentage changes from baseline in serum IGF-I levels after administration of a single sc dose of placebo (•, n = 3 in each dose group, total n = 12) and four increasing doses ({diamondsuit}, 0.03 mg/kg; •, 0.1 mg/kg; {blacksquare}, 0.3 mg/kg; {blacktriangleup}, 1.0 mg/kg; n = 6 each dose) of B2036-PEG in young men. Serum IGF-I levels decreased in a dose-dependent manner, with a maximal 49 ± 6% decrease, 5 days after administration of the highest dose of 1.0 mg/kg B2036-PEG (P < 0.001 vs. placebo on day 5).

 
Serum GH levels did not change substantially, in response to administration of any of the B2036-PEG doses studied. Both the indirect GH chemiluminescence assay and the direct two-site GH immunoassay agreed well and gave effectively the same results. None of the mean GH concentration time series (after any of the four B2036-PEG doses) showed any elevation, relative to placebo, at any of the time points examined, except for a statistically significant (ANOVA), albeit extremely small, rise in mean GH levels, beyond 48 h after 1.0 mg/kg B2036-PEG (in the results from the direct assay). Fig. 7Go shows the mean GH levels measured by both the indirect and direct GH assays after administration of placebo (n = 12) and the highest dose, 1.0 mg/kg B2036-PEG (n = 6).



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  		Figure 7. Mean (± SE) GH concentrations (µg/L) over 144 h, in response to a single sc dose of placebo (n = 12; dotted line) or 1.0 mg/kg B2036-PEG (n = 6; solid line), as assessed by indirect (University of Virginia, upper panel) and direct (Munich, lower panel) GH assays.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The GH-R is a member of the cytokine receptor superfamily, which includes the receptors for many of the interleukins, colony-stimulating factors, erythropoietin, oncostatin M, leukemia inhibitory factor, ciliary eurotrophic factor, and PRL (for review, see Ref. 11). These receptors share many common features, including either homo- or heterodimerization of receptor subunits. A series of biophysical studies by Cunningham et al. (12) and crystal structure analysis by deVos et al. (13) showed that recombinant human GH (rhGH) has two binding sites for the extracellular domain of the GH-R, the GH-binding protein (GHbp). Their data support a model of sequential binding whereby one GHbp binds to site 1 on the GH molecule; and then a second molecule of GHbp binds to site 2 on GH, forming a GH:(GHbp)2 complex. Although monomers of one GHbp bound to site 1 were detected, there is no evidence for monomers of GHbp bound only to site 2 of GH. Furthermore, competition studies showed that excess wild type rhGH, as well as a protein containing an engineered site 1 of binding, were able to disrupt dimer formation; whereas a GH mutant having an intact site 2, but a defective site 1, was not able to disrupt dimerization. Most importantly, recombinant GH molecules, mutated in either site 1 or site 2 of binding, were used in a number of in vitro assays, in order to determine the role of GH-R dimerization in intracellular signaling (14). Dimerization of the receptor is essential for signaling at the cellular level and therefore points to the role of GH antagonists (which inhibit this dimerization) in the treatment of the clinical symptoms of GH excess.

GH secretion is regulated by short-loop GH feedback at the hypothalamic level. The degree to which this occurs has been difficult to determine. The development of a GH analog that acts as a GH antagonist offers the first opportunity to define the role of GH in this short-loop feedback.

We anticipated that the antagonist would stimulate GH secretion, because there is abundant data to demonstrate that GH tonically inhibits its own secretion (1, 15, 16). There is also evidence that GH short-loop feedback occurs at the hypothalamic level, and no evidence for GH short-loop feedback at the pituitary level (4, 17, 18). GH stimulates SRIF production in the hypothalamus, particularly in the periventricular nucleus (2). SRIF neurons project both to the arcuate nucleus and synapse at GHRH neurons to inhibit their firing (19). SRIF neurons also project to the median eminence, where SRIF is released into the portal capillaries to act at the somatotroph to inhibit GH release. It would be anticipated that GH stimulation would occur early, before the suppression of serum IGF-I levels, which are significant only at 48–72 h. This relates to the long half-life of IGF-I in the circulation.

The observed B2036-PEG-dependent reduction in serum IGF-I levels supports the concept that B2036-PEG acts by blocking GH signal transduction in the periphery. The lack of marked stimulation of GH secretion is important, both from a theoretical and a practical perspective. Although this study was performed under controlled conditions, the lack of frequent sampling of GH and strict timing of food intake, limits any conclusions regarding subtle changes in GH secretion. It is possible, however, that the slight increase in mean GH (<1.0 µg/L) observed in the direct assay after 48 h may be a consequence of reduced negative IGF-I feedback at the pituitary. Additional studies to fully determine the impact on GH release are warranted and should employ the direct assay for measurement of endogenous GH levels.

We speculate that B2036-PEG cannot access the site where GH feedback occurs, i.e. in the hypothalamus. This could occur if the site is within the blood brain barrier. As a consequence of its PEG-modification, B2036-PEG behaves as if it were a much larger molecule than GH and, thus, may not be able to cross the blood brain barrier. The practical importance of this observation is that B2036-PEG is being developed as a treatment for acromegaly. If indeed it does not cross to the site of GH feedback, then it is unlikely that it would further stimulate GH secretion by reversing GH feedback. Thus, there seems to be little danger of producing a clinical state analogous to that of Nelson’s syndrome after bilateral adrenalectomy for Cushing’s disease. Preliminary phase II studies of B2036-PEG in acromegaly give hope that this may be an effective therapy; phase III studies in acromegalic patients are underway.


   Acknowledgments
 
We thank Bruce Gaylinn, Ph.D., and Charles Lyons at the University of Virginia for performance of the HPLC analyses; the Core Laboratory of the General Clinical Research Center for performance of the GH chemiluminescence assays; and Emily Skiles for assistance with graphics.


   Footnotes
 
1 Presented, in part, as an abstract at the 80th Annual Meeting of The Endocrine Society, New Orleans, LA, June 24–27, 1998. This work was supported, in part, by NIH Grant RR-00847 (to the University of Virginia General Clinical Research Center), the National Science Foundation Center for Biological Timing Grant DIR-8920162 (to M.S.), and NIH Grant DK-32632 (to M.O.T.). Back

Received December 4, 1998.

Revised February 17, 1999.

Accepted February 26, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Abe H, Molitch ME, Van W, Underwood LE. 1983 Human growth hormone and somatomedin C suppress the spontaneous release of growth hormone in unanesthetized rats. Endocrinology. 113:1319–1324.[Abstract/Free Full Text]
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  3. Chomczynski P, Downs TR, Frohman LA. 1988 Feedback regulation of growth hormone (GH)-releasing hormone gene expression by GH in rat hypothalamus. Endocrinology. 2:236–241.
  4. Szabo M, Butz MR, Banerjee SA, Chikaraishi DM, Frohman LA. 1995 Autofeedback suppression of growth hormone (GH) secretion in transgenic mice expressing a human GH reporter targeted by tyrosine hydroxylase 5'-flanking sequences to the hypothalamus. Endocrinology. 136:4044–4048.[Abstract]
  5. Chapman IM, Hartman ML, Pezzoli SS, et al. 1997 Effect of aging on the sensitivity of growth hormone secretion to insulin-like growth factor (IGF)-I negative feedback. J Clin Endocrinol Metab. 82:2996–3004.[Abstract/Free Full Text]
  6. Olsen K, Gehant R, Mukku V, et al. 1997 Preparation and characterization of poly(ethylene glycol)ylated human growth hormone antagonist. In: Harris JM, Zalipsky S, eds. Poly(ethylene glycol). Chemistry and biological applications. Washington, DC: American Chemical Society; 170–181.
  7. Zalipsky S, Lee C. 1992 Use of functionalized polyethylene glycols for modification of polypeptides. In: Harris JM, ed. PEG chemistry: biotechnical and biomedical applications. New York: Plenum Press; 347–370.
  8. Clark R, Olson K, Fuh G, et al. 1996 Long-acting growth hormones produced by conjugation with polyethylene glycol. J Biol Chem. 271:21969–21977.[Abstract/Free Full Text]
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  10. Chapman IM, Hartman ML, Straume M, Johnson ML, Veldhuis JD, Thorner MO. 1994 Enhanced sensitivity growth hormone (GH) chemiluminescence assay reveals lower postglucose nadir GH concentrations in men than women. J Clin Endocrinol Metab. 78:1312–1319.[Abstract]
  11. Wells JA, de Vos AM. 1996 Hematopoietic receptor complexes. Annu Rev Biochem. 65:609–634.[CrossRef][Medline]
  12. Cunningham BC, Ultsch M, de Vos AM, Mulkerrin MG, Clauser KR, Wells JA. 1991 Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science. 254:821–825.[Abstract/Free Full Text]
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  14. Wells J. 1994 Structural and functional basis for hormone binding and receptor oligomerization. Curr Opin Cell Biol. 6:163–173.[CrossRef][Medline]
  15. Tannenbaum GS. 1980 Evidence for autoregulation of growth hormone secretion via the central nervous system. Endocrinology. 107:2117–2120.[Abstract/Free Full Text]
  16. Pellegrini E, Carmignac DF, Bluet-Pajot MT, et al. 1997 Intrahypothalamic growth hormone feedback: from dwarfism to acromegaly in the rat. Endocrinology. 138:4543–4551.[Abstract/Free Full Text]
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Binding and Functional Studies with the Growth Hormone Receptor Antagonist, B2036-PEG (Pegvisomant), Reveal Effects of Pegylation and Evidence That It Binds to a Receptor Dimer
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H.E. Turner and J.A.H. Wass
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