Anti-GnRH Receptor Monoclonal Antibodies, First-In-Class GnRH Analog

Lee G,Chow Sn,Chien Ch,Liu S

doi:10.15744/2454-3284.1.102

Abstract

A monoclonal antibody (Mab) designated as GHR106 was generated against the extracellular domain (N1-29 synthetic peptide) of human gonadotropin releasing hormone (GnRH) receptor. It is a first-in-class GnRH analog and can serve as a drug candidate for potential applications in the treatment of human cancers and/or fertility regulations. Both Mabs in murine (mGHR106) or humanized (hGHR106) forms were shown to have comparable specificity and affinity to intact GnRH receptor on cancer cells or to N1-29 synthetic peptides from humans and monkeys. Similar to decapeptide GnRH analogs, both Mabs were shown to induce apoptosis to cultured cancer cells of various tissue origins, including those from the ovary, breast, prostate, and lung. However, both Mabs were also found to induce complement-dependent cytotoxicity (CDC) reaction for lysis of cancer cells, an immune property which is not shared by peptide analogs of GnRH. By using semi-quantitative reverse transcription polymerase chain reaction (RT-PCR), both GHR106 Mabs and the GnRH decapeptide antagonist, Antide, were shown to be bioequivalent in terms of their respective effects on genes involved in the proliferation and apoptosis of cancer cells. In addition, GHR106 Mabs have a much longer circulating half-life than GnRH peptide analogs (days versus hours). Based on the results of these studies, it can be concluded that both mGHR106 and hGHR106 are bioequivalent to the GnRH decapeptide antagonist, Antide, in many biological and functional properties. Therefore, hGHR106 can serve as a long-acting alternative to the current decapeptide GnRH antagonists for therapeutic treatments in the immunotherapy of human cancers, including those of gynecologic origin.

Highlights

Gonadotropin releasing hormone (GnRH), both types I and II, is a decapeptide hormone that stimulates the release of gonadotropin, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary through specific binding to the gonadotropin releasing hormone (GnRH) receptor located on the external membrane of selected cell types [1,2,3]
Generation and characterization of monoclonal antibodies against human GnRH receptor Based on the results of these binding assays, the dissociation constant (Kd) between GHR106 and GnRH receptor, or the corresponding N1-29 synthetic peptide was estimated to be 2 x 10-9M [34]
Through contract research service (CRO) by LakePharma Inc., Murine form of GHR106 (mGHR106) was humanized to hGHR106. hGHR106 was shown to have an affinity constant which was similar to that of the original mGHR106 to the GnRH receptor on well-bound cancer cells [27]

Summary

Introduction

Gonadotropin releasing hormone (GnRH), both types I and II, is a decapeptide hormone that stimulates the release of gonadotropin, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary through specific binding to the GnRH receptor located on the external membrane of selected cell types [1,2,3]. Anti-proliferation effects of GnRH or its analogs on cancer cells of different human tissue origins have been reported and have been the molecular basis for cancer therapy [4,7,8,9]. Numerous clinical studies have reported the use of cytotoxic GnRH analogs or GnRH analogs alone as anti-cancer drugs [10]. GnRH analogs are sometimes formulated by covalently linking cytotoxic anti-cancer agents, such as AN-152 or AN-207, to GnRH or its analogs. Limited and variable efficacy was observed in many cases. This approach has been shown to be effective in cancer treatments with a lower toxicity and improved efficacy when compared to non-targeted systemic chemotherapy [11]. GnRH analogs have been used for the treatment of other estrogen-dependent conditions, such as endometriosis, uterine fibroids, and endometrial thinning, to treat precocious puberty, and to control ovarian stimulation in in vitro fertilization (IVF) [11]

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Conclusion