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Neutralizing prolactin receptor antibodies and their therapeutic use

A prolactin receptor, antibody technology, applied in the direction of antibody medical components, antibodies, anti-receptor/cell surface antigen/cell surface determinant immunoglobulin, etc., can solve problems such as interference with PRLR-mediated signal transduction

Inactive Publication Date: 2012-10-17
BAYER IP GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Currently, it is not possible to completely interfere with PRLR-mediated signaling

Method used

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  • Neutralizing prolactin receptor antibodies and their therapeutic use
  • Neutralizing prolactin receptor antibodies and their therapeutic use
  • Neutralizing prolactin receptor antibodies and their therapeutic use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0379] Example 1 Isolation of target-specific antibodies from a human antibody phage display library

[0380] To isolate a panel of antibodies capable of neutralizing the activity of human PRLR, three human antibody phage display libraries expressing Fab and scFv fragments were studied in parallel. The target used for library panning was the soluble extracellular domain (ECD) of the prolactin receptor (human prolactin receptor amino acids 25-234) prepared as described above in WO08 / 022295 (Novartis). Alternative targets are the ECD of PRLR, whose C-terminus is linked to 6 histidines or via an amino acid sequence "isoleucine-glutamic acid-glycine-arginine-methionine-aspartic acid" The linker was attached to the human IgG1-Fc domain.

[0381] Selection of target-specific antibodies from phage display was performed according to the method described by Marks et al. (Methods Mol Biol. 248:161-76, 2004). Briefly, phage-displayed libraries were incubated with 50 pmol biotinylated E...

Embodiment 2

[0384] Example 2 Quantitative Analysis of Prolactin and Prolactin Receptor Gene Expression in Orthotopic and Ectopic Endometrium and Endometriosis Lesions from Patients and Healthy Controls by Real-Time TaqMan PCR Analysis

[0385] Real-time Taqman PCR analysis was performed using the ABI Prism 7700 Sequence Detector System according to the manufacturer's instructions (PE Applied Biosystems) and as described (Endocrinolgy 2008, 149(8):3952-3959) and known to those skilled in the art . Relative expression levels of PRL and PRLR were normalized to cyclophyllin expression. We utilized quantitative real-time Taqman PCR analysis to analyze the expression of PRL and PRLR in endometrium from healthy women as well as endometrium and endometriotic lesions from patients. The expression of prolactin and its receptor is significantly upregulated in endometriotic lesions compared with healthy endometrium or endometrium derived from patients.

[0386] The result is as figure 1 and 2 sh...

Embodiment 3

[0388] Example 3 Analysis of Prolactin Receptor Expression in Human Tissues by Northern Blot

[0389] RNA was isolated from different rat tissues and transferred to nylon membranes after gel electrophoresis. The membrane was sequentially hybridized with radiolabeled cDNA of rat prolactin receptor or β-actin (as a loading control), washed and exposed to film. Bands correspond to rat prolactin receptor and β-actin mRNAs. image 3 The results shown show strong expression of prolactin receptors in the placenta, prostate, ovary and adrenal gland.

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PUM

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Abstract

The present invention is directed to neutralizing prolactin receptor antibodies 002-H06 and antigen binding fragments, pharmaceutical compositions containing them and their use in the treatment or prevention of benign disorders and indications mediated by the prolactin receptor such as endometriosis, adenomyosis, non-hormonal female contraception, benign breast disease and mastalgia, lactation inhibition, benign prostate hyperplasia, fibroids, hyper- and normoprolactinemic hair loss, and cotreatment in combined hormone therapy to inhibit mammary epithelial cell proliferation. The antibodies of the invention block prolactin receptor-mediated signaling.

Description

technical field [0001] The present invention relates to prolactin receptor antibody 002-H06, and provides recombinant antigen binding regions and antibodies and functional fragments comprising such antigen binding regions, which specifically bind and neutralize prolactin receptors; nucleic acid sequences encoding the aforementioned antibodies; Carriers comprising said nucleic acid sequences; Pharmaceutical compositions comprising them and their use in the treatment or prevention of benign diseases and indications that benefit from the inhibition of prolactin receptor-mediated signal transduction, Examples include endometriosis, adenomyosis, nonhormonal female contraception, benign breast disease, mastalgia, lactation suppression, benign prostatic hyperplasia, fibroids, and hyperprolactinemic and normoprolactinemic alopecia; As well as synergistic therapy in combination hormone therapy to inhibit breast epithelial cell proliferation. Background technique [0002] There is an...

Claims

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Application Information

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IPC IPC(8): C07K16/28A61K39/395A61P35/00A61P5/08
CPCC07K16/2866C07K2317/565C07K16/2869C07K16/28A61K39/3955A61K2039/505C07K2317/73C07K2317/56C07K2316/96A61K45/06C07K2317/76A61P13/08A61P15/00A61P15/02A61P15/08A61P15/14A61P15/18A61P17/14A61P21/00A61P29/00A61P35/00A61P43/00A61P5/00A61P5/08A61P5/10A61P5/24A61P5/30C07K16/30
Inventor C·奥托S·沃尔夫C·弗莱贝格A·哈尔恩加S·格雷文M·特劳特魏茵S·布鲁德
Owner BAYER IP GMBH
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