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Humanized Anti-GnRH Receptor Monoclonal Antibody

The First-In-Class GnRH Analog for Human Cancers Immunotherapy

Home / Pipeline / Humanized Anti-GnRH Receptor Monoclonal Antibody

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Drug Name hGHR106
Description

Humanized GHR106 monoclonal antibody (hGHR106) was generated against the extracellular domain (N1-29) of the gonadotropin-releasing hormone (GnRH) receptor. It belongs to a new class of bioequivalent long-acting GnRH analogs, and can serve as an alternative to the current GnRH decapeptide antagonists for cancer immunotherapy and fertility regulation.

hGHR106 has comparable specificity and affinity to intact GnRH receptors on cancer cells and N1-29 synthetic peptides of humans and monkeys. It is a bioequivalent to Antide (a GnRH decapeptide antagonist) in terms of their respective effects on the expression of genes related to cell proliferation and apoptosis. hGHR106 has shown to act in a similar manner to the decapeptide Antide, in inducing the apoptosis of cultured cancer cells from various tissue origins. Furthermore, hGHR106 was found to induce complement-dependent cytotoxicity (CDC) reaction to cancer cells, an immune property which is not shared by decapeptide GnRH analogs. As a monoclonal antibody, hGHR106 demonstrates a remarkably longer circulating half-life than GnRH peptide analogs (days vs. hours).

Indication Cancers; Reproductive diseases
Target Gonadotropin-releasing hormone receptor (GnRHR)
Product Category Humanized monoclonal antibody; Cancer immunotherapy; Fertility regulation
Mechanism of Action By binding to GnRHR in multiple tumor cells, GHR106 induces cellular apoptosis and cytolysis (anti-GnRH).
Status Preclinical
Patent Ten patents on hGHR106 have been granted in the United States, France, Switzerland, and etc.

Collaboration Opportunity

Protheragen Inc. is actively seeking partnership to further develop hGHR106. Potential collaboration can be strategic alliance, licensing, or marketing agreement.

We look forward to hearing from you.

Gonadotropin-Releasing Hormone Receptor (GnRHR)

Introduction This gene encodes the receptor for type 1 gonadotropin-releasing hormone. GnRHR is a member of the seven-transmembrane receptors, belonging to G-protein coupled receptor (GPCR) family. GnRHR is expressed on the surface of pituitary gonadotrope cells as well as breast, ovary, lymphocytes and prostate cells. After binding to gonadotropin-releasing hormone, the receptor associates with G-proteins to activate a phosphatidylinositol-calcium second messenger system. Activation of the GnRHR ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). The lack of this gene can lead to hypogonadotropic hypogonadism (HH). Alternative splicing causes multiple transcript variants to encode different isoforms. For this gene, more than 18 transcription initiation sites were identified in the 5′ region and multiple polyA signals were in the 3′ region.
Approved Name Gonadotropin releasing hormone receptor [ Homo sapiens (human) ]
Official Symbol GnRHR
Gene Type Protein coding
Synonyms HH7; GRHR; LRHR; LHRHR; GnRHR1
Ensembl ENSG00000109163
Gene ID 4421
mRNA Refseq NM_000406.2;  NM_001012763.1
Patent Ten patents about hGHR106 have been granted in the United States, France, Switzerland, and etc.
Protein Refseq NP_000397.1;  NP_001012781.1
OMIM 138850
UniProt ID P30968
Chromosome
Location
4q13.2

Clinical Resources

Gene Function

The growth of sex hormone-dependent tumors is inhibited by analogs of GnRH. GnRH agonists suppress the pituitary-gonadal function, which results in the deficiency of sex-steroid in order to treat prostatic and breast cancers. In addition, GnRH agonists and antagonists exert a direct effect on these tumors that is mediated by specific high-affinity GnRH receptors found on these cells. GnRH agonists and antagonists also suppress the growth of pancreatic cancers. Szende et al. (1991) demonstrated that pancreatic tumor cells exhibit high-affinity binding sites for GnRH, but only in their nuclei; low-affinity sites are associated with the cell membranes. These binding sites appear to be GnRH receptors since electron microscopic immunohistochemistry showed that the antibody against GnRH receptor reacted in the nucleus of pancreatic tumor cells.

Maji et al. (2009) found that peptide and protein hormones, including GnRH, in secretory granules of the endocrine system are stored in an amyloid-like cross-beta-sheet-rich conformation. They concluded that functional amyloids in the pituitary and other organs can contribute to normal cell and tissue physiology.

Pathway G-protein-coupled receptor signaling pathways
Major Conditions Pain;
Disorders of sexual function, breast and reproduction;
Neurological disorders;
AIDS;
Genitourinary disorders;
Endocrine disorders;
Congenital defects;
Cancer;

Humanized GHR106 monoclonal antibody (hGHR106) is a bioequivalent alternative to GnRH decapeptide analogs. As a GnRH antagonist, it can block the pituitary-gonadal axis to treat female reproductive diseases. GnRH antagonist has also been applied for in-vitro fertilization or reducing estrogen levels to suppress endometriosis-associated pelvic pain. In order to preserve fertility in female patients undergoing chemotherapy, GnRH antagonists are usually utilized to minimize the risk of ovarian stimulation.

In addition, experimental evidence indicated that in tumors, activation of type I GnRH receptors consistently decreases cell proliferation, mainly by interfering with the mitogenic activity of stimulatory growth factors (e.g., EGF, IGF).

Thus, we are developing hGHR106 to 1). treat reproductive diseases and 2). use in cancer therapy.

Cancer

Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Over 100 types of cancers affect humans. Chemotherapy, radiation, and/or surgery are the main cancer treatments. About 14.1 million of new cases occur every year, with the death rate of 15.7%, excluding skin cancer other than melanoma.

As more people live to old age and because of the changing lifestyles, the number of cancer patients are growing quickly. In 2017, the costs of cancer treatment in the United States were $147.3 billion. With the widespread expressions of GnRHR among various human cancer, hGHR106 can be a bioequivalent alternative to GnRH decapeptide analogs and therefore serve as an anti-cancer drug. Among the cancers, lung, breast, and prostate cancers are the top 3 cancer types worldwide.

Category Target GnRHR for Treatment of Cancers
Hormone-Related Cancer Uterine leiomyoma; Breast metastatic cancer; Fallopian tube; Ovary; Endometrium; Prostate
Non hormone-related Cance Peritoneum; Skin; Melanoma; Bladder; Hematologic-blood; Lung

Lung Cancer According to the global cancer statistics for 2018, the incidence for lung cancer was 2,093,867, including 11.6% of new cancer cases. Non-small cell lung cancer and small cell lung cancer are two main types of lung cancer. 5 types of standard treatment for lung cancer are surgery, chemotherapy, radiation therapy, immunotherapy, and laser therapy. Moreover, endoscopic stent placement can be used to open a blocked airway by small cell lung cancer. For treating non-small cell lung cancer, targeted therapy, photodynamic therapy (PDT), cryosurgery and electrocautery are also the options.
Breast Cancer In 2018, about 2,088,849 people worldwide suffered from breast cancer and the death toll was about 626,679. Survival rates of breast cancer in the developed countries are high and most of the patients would survive for at least 5 years. Depending on the specifics, appropriate treatment options can be used, including chemotherapy, hormonal therapy and targeted therapy.
Prostate Cancer Globally, prostate cancer is the second highest morbidity and mortality rate following lung cancer in men. In 2018, there were 1,276,106 new cases of prostate cancer, accounting for 7.1% of the total number of new cancer patients, with death toll reached 358,989. The 5-year survival rate in the developed countries is high. For prostate cancer, the common treatments include surgery, radiation therapy, hormone therapy, vaccine or chemotherapy.

Reproductive Disease

Infertility by Chemotherapy In women, chemotherapy drugs can stop the ovaries from working properly and releasing eggs (ovulation). The damaged ovaries and loss of healthy eggs can lead to early menopause, which may be temporary or permanent. In order to protect the fertility of female cancer patients, it is an ideal method to prevent the maturation of eggs in female ovaries. Some research studies show that using GnRH drugs during chemotherapy may help protect a woman’s ovaries and fertility.
In vitro Fertilization for Infertility IVF is a type of assisted reproductive technology applied for infertility treatment and gestational surrogacy. In 2018, 8 million infants had been born through IVF and other assisted reproductive ways. During IVF, suppression of spontaneous ovulation can be used for generating multiple eggs, for which either a GnRH agonist protocol or a GnRH antagonist protocol is available.
Endometriosis Endometriosis is a disease that the endometrial tissues are located outside of the uterus. Incidences of endometriosis occur mostly in postmenopausal women, rarely seen in younger adults before reaching the menarche. The rate of recurrence is estimated to be 40-50% for female over a 5-year period. Pelvic pain and infertility are the main results of endometriosis. For endometriosis, there is no cure but some treatments for pelvic pain, such as pain relievers, hormone therapy, and surgical treatments for severe pain. In hormone therapy, GnRH antagonists can reduce estrogen levels to relieve pain caused by endometriosis.

Antitumor Activity Stimulated Through Receptor Binding

GHR106 binds to GnRHR and competitively blocks the activation. At the pituitary level, it causes a rapid and sustained inhibition of the pituitary–gonadal functions without inducing the suppressive flare effect.

By targeting GnRHR in multiple tumor cells, GHR106 induces cellular apoptosis and cytolysis to achieve antitumor activity. In cancer cells, Gαi is the major G protein coupled with GnRHR, mediating antitumor effects through the inhibition of cAMP accumulation. Coupling of the GnRHR to Gαi is followed by the activation of intracellular MAPK signaling cascades, a downstream mediator of the antiproliferative/proapoptotic activity.

The Patent Status of hGHR106

Currently, ten patents on hGHR106 have been granted worldwide, including the United States, France, Switzerland, etc. Multi-angle and multi-level patent protection barriers will be built completely.

1 H40 L42 2 H64 L42
3 H65 L42 4 H66 L42
5 Control
Reducing conditions

mGHR106 was Successfully Humanized in Four Rounds

Recombinant antibodies with newly designed heavy chains from the four rounds of selection exhibited the same molecular weight on the Western blots in comparison to the parental heavy chain.

The objective of the humanization is to minimize immunogenicity and maximize the preservation of antigen binding affinity and specificity of the resulting antibodies.


Negative Controls (Lanes 1 to 4).Lane 1: no treatment; Lane 2: freshly prepared rabbit baby complement; Lane 3: normal human IgG (plus complement); Lane 4: normal mouse IgG (plus complement); Lane 5: hGHR106 (plus complement) Lane 6: mGHR106 (plus complement)

Lysis of Cancer Cells by Complement-Dependent Cytotoxicity (CDC) Reactions

Specific binding to cancer cell surface bound GnRHR, both mGHR106 and hGHR106 at 10μg/mL induce CDC reaction in a similar and significant level to result in cell lysis in the presence of complement.

Comparative Studies of Induced Apoptosis to Cultured Cancer Cells

40-65% increase in apoptosis of treated cancer cells was found upon 24 to 48 hrs incubation with mGHR106, hGHR106, or Antide (a GnRH decapeptide antagonist).

Immunohistochemistry Assays

IHC staining revealed that both mGHR106 and hGHR106 react with fixed OC-3-VGH ovarian cancer cells.

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