AMHR2（Anti-Müllerian hormone receptor）is a key receptor in the transforming growth factor-β (TGF-β) superfamily. In recent years, it has become a research hotspot for targeted therapies for a variety of diseases, particularly reproductive endocrine disorders (such as polycystic ovary syndrome) and tumors (such as ovarian cancer and lung cancer). Treatment strategies primarily target the AMH-AMHR2 signaling pathway to modulate downstream biological effects.
(Data source: Chauvin M, et al. Cell Rep. 2023)
Expression distribution of AMHR2
AMHR2 is expressed in mesenchymal cells surrounding the epithelium of Müllerian ducts (MDs) in both sexes and disappears after resolution of MDs in males. AMHR2 is also expressed in the gonads of both males and females. In the testis, AMHR2 is expressed from fetal development to puberty, while in the ovary, AMHR2 is expressed by granulosa cells of preantral and antral follicles from fetal development to adulthood.
(Data source: Uniprot)
The structure of AMHR2 and its receptor
The human AMHR2 gene consists of 11 exons and is located on chromosome 12q13. It encodes a 573-amino acid membrane protein containing a signal sequence, an N- terminal extracellular domain that binds to AMH, a single transmembrane domain, and an intracellular domain with serine/threonine kinase activity. AMHR2 utilizes its transmembrane domain for insertion and targeting at the cell membrane, as its signal sequence is nonfunctional. The extracellular domain has the structure of a three-finger toxin found in other TGF-β type II receptors, with four similar disulfide bonds. Molecular modeling suggests that the intracellular domain has the structure of a two-domain kinase .
The receptor binding interaction between AMH and AMHR2 is unique within the family, with a distinct steric offset, extended Finger 1 conformation, salt bridges, and backbone hydrogen bonds enabling highly specific binding within the family. AMHR2's Finger 1 is five residues longer than other type II receptors, forming parallel β-sheets that hydrogen-bond to the Finger 4 backbone of AMH.
(Data source: Hart KN, et al. Proc Natl Acad Sci USA. 2021)
Signaling pathway and regulation of AMHR2
AMH binds to its receptor, AMHR2, phosphorylating and activating the kinase domain of type I receptors (ALK2 or 3), which then phosphorylate Smad1, 5, and 8. Phosphorylated Smads form heterotrimers with Smad4, which translocates to the nucleus and associates with other transcription factors (TFs). The Smad/TF complex binds to the promoter or enhancer regions of target genes to regulate transcription.
(Data source: Gowkielewicz M, et al. Front Endocrinol (Lausanne). 2024)
Targeted therapy for AMHR2
Murlentamab is a humanized IgG1 monoclonal antibody targeting AMHR2. It has high affinity for both AMHR2 on tumor cells and CD16 on macrophages, exhibiting antibody-dependent cell-mediated ADCC and ADCP, and can reduce TAM inhibitory T cell function, thereby exerting anti-tumor effects. Murlentamab is currently in Phase I (C101, NCT02978755) and Phase IIa (C201, NCT01668784) clinical trials for patients with advanced or metastatic gynecological cancers (such as ovarian cancer) and colorectal cancer. However, the Phase II study was terminated prematurely due to poor efficacy.
