GHR106, the First in Class Antibody-based GnRH Antagonist for Broad Clinical Applications
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Abstract
During the last two decades, our laboratory has identified and studied a GHR106 monoclonal antibody which was generated against N1-29 oligopeptide located in the extracellular domains of human GnRH receptor. GHR106 was shown to exhibit bioactivities as GnRH antagonist, similar to those of small molecules such as Cetrorelix and Elagolix, except that former has a much longer half-life (days vs. hours). Previous studies have indicated that GnRH receptor is localized mainly in anterior pituitary and placenta during pregnancy as well as other reproduction-related tissues in minor amount. It was also known that GnRH receptor is highly expressed among different cancer cells. By using GHR106 and other GnRH antagonists as the target probe, the biological functions of GnRH receptor were found to be tissue-dependent. When acting on the pituitary receptor, GHR106 can cause reversible suppressions of reproductive hormones, such as gonadotropins, E2 and progesterone, whereas HCG and E2, progesterone were suppressed upon targeting to placental GnRH receptor to cause pregnancy terminations. Therefore, we believe that GHR106 is a suitable long acting GnRH antagonist for control of fertility regulations and terminations of ectopic pregnancy and can be used to treat numerous related gynecological diseases. On the other hand, when targeting the same receptor on cancer cells, GHR106 will induce cellular apoptosis to almost all cancer cells. Therefore, GHR106 is also beneficial to immunotherapeutic applications of many human cancers, irrespective of their hormone dependence. Additional modifications of this unique antibody are likely in the future, including CAR (chimeric antigen receptor)-T cell constructs, bispecific antibody formulations and/or antibody drug conjugates. Based on our comprehensive studies, GHR106 can be developed into antibody drugs of multi-indications and could be more beneficial to the existing small molecular GnRH antagonists.
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