Preparation of Superactive Prolactin Receptor Antagonists

Author:

Solomon Gili1,Oclon Ewa2,Hayouka Zvi1,Gertler Arieh1ORCID

Affiliation:

1. The Robert H. Smith Faculty of Agriculture, Food and Environment, Hebrew University of Jerusalem , Rehovot 76100 , Israel

2. Center for Experimental and Innovative Medicine, Laboratory of Recombinant Proteins Production, University of Agriculture in Krakow , Krakow , Poland

Abstract

Abstract Most breast cancer deaths are caused by malignant estrogen receptor–positive breast tumors that later recur as metastatic disease. Prolactin (PRL) has been documented as a factor promoting breast cancer development and metastasis. We therefore developed superactive prolactin receptor (PRLR) antagonists aimed at blocking PRL action. We purified 12 novel mutants to homogeneity as monomers, and the most potent antagonist was over 95-fold more active than the previously reported weak antagonist, the mutant Del 1-9 human PRL G129R. This enhanced antagonistic activity resulted mostly from prolonged interaction with the extracellular domain (ECD) of PRLR. All mutants were properly refolded, as indicated by interaction with human PRLR-ECD and by circular dichroism analysis. We then prepared monopegylated variants of the most active mutants to extend their biological half-life in vivo.

Publisher

The Endocrine Society

Subject

Endocrinology

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