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Parathyroid hormone variants

A parathyroid hormone and variant technology, applied in the direction of parathyroid hormone, hormone peptides, antibody mimics/stents, etc., can solve problems such as poor control, short half-life, daytime serum calcium fluctuations, etc.

Pending Publication Date: 2021-12-24
TAKEDA PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to its short in vivo half-life, the human pharmacokinetic profile of NATPARA exhibits rapid clearance and a peak-to-trough ratio, which results in significant diurnal serum calcium fluctuations and paracalciuria (a condition associated with elevated urinary calcium levels) disease) poor control

Method used

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Examples

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example

[0210] The following examples illustrate certain aspects of the specification. These examples should not be construed as limiting, as these examples merely provide a specific understanding and practice of the embodiments and their various aspects.

example 1

[0211] Example 1: Production and purification of Fc fusion PTH variants (PTH-66 as an example)

[0212] PTH-66 was transiently expressed in CHO cells and the conditioned medium was stored at -20°C until further use. Thaw conditioned media in a 25 °C water bath and filter through a 0.2 µm bottle top filter unit. PTH-66 protein was purified on protein A derivatized resin MabSelect SuRe following the manufacturer's protocol (Figure 8). MabSelect SuRe columns were pre-equilibrated with PBS. Thawed conditioned medium was loaded onto the column and washed extensively with PBS. PTH-66 protein was eluted by step elution with 100 mM sodium citrate buffer, pH 3.2. Eluted fractions were analyzed on SDS-PAGE (Figure 9). The pH of the pooled eluted fractions was raised to about pH 6 with 1M Tris pH 10. The neutralized pooled elution fractions were dialyzed into PTH-66 storage buffer 20 mM sodium phosphate buffer, 50 mM sodium chloride, 26 mg / ml mannitol, pH 6.0, and stored at -80°C. ...

example 2

[0216] Example 2: Effect of C-terminal truncation of PTH-Fc fusions

[0217] PTH-Fc fusion variants comprising truncated PTHs of different lengths were prepared according to the method outlined in Example 1. The following PTH-Fc fusion variants were generated: PTH-66 (PTH(1-74)-Fc), PTH-67 (PTH(1-64)-Fc), PTH-68 (PTH(1-54)-Fc ), PTH-69 (PTH(1-44)-Fc) and PTH(1-34)-Fc.

[0218] After a single subcutaneous treatment of Spraque-Dawley rats with truncated variants and full-length PTH(1-84)-Fc at 0.25 mg / kg was assessed using the Immunotopics Bioactivity ELISA Kit (60-3000). Serum concentration of PTH, and results in figure 1 shown in .

[0219] Such as figure 1 As shown, C-terminal truncation of PTH surprisingly and unexpectedly improves the exposure and pharmacokinetics of PTH-Fc fusions.

[0220] As shown, the truncated PTH-Fc fusion variants of the present invention are superior to native length PTH(1-84)-Fc fusions and teriparatide-Fc (PTH(1-34)-Fc fusions) . Even mor...

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Abstract

The invention relates to parathyroid hormone (PTH) variants and pharmaceutical compositions comprising same. The invention further relates to PTH compositions with improved serum half-life and peak-trough ratios, and methods of controlling serum calcium levels with the PTH variants and compositions of the invention. The invention further relates to methods of treating hypoparathyroidism and / or hypocalcemia due to hypoparathyroidism with the PTH variants and compositions of the invention.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 798,113, filed January 29, 2019, U.S. Provisional Application No. 62 / 800,744, filed February 4, 2019, and U.S. Provisional Application No. 62, filed August 9, 2019 / 884,730, the disclosure of which is incorporated herein by reference in its entirety. technical field [0003] The present invention relates to parathyroid hormone variants and compositions comprising the same. The invention further relates to parathyroid hormone variants and compositions having improved serum half-life, and methods of controlling serum calcium levels using the parathyroid hormone compositions of the invention. Background technique [0004] Parathyroid hormone (PTH), an 84-amino acid product secreted by the mammalian parathyroid gland, controls serum calcium levels through its effects on various tissues, including bone. Studies in humans with certain forms of PTH have shown that...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/56C07K14/575A61P5/18
CPCA61P5/18A61K38/00C07K14/635C07K2319/02C07K2319/30C07K2319/50C07K2319/21A61K9/0019A61K9/08C12N15/62C12N15/85C07K1/165A61K9/0014
Inventor C·潘A·诺顿K·霍姆斯D·劳埃德B·古德温R·史S·贾殷C·沈
Owner TAKEDA PHARMA CO LTD
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