Mucin-16 (MUC16) membrane-proximal region (MUC16-C)

Mucin-16 (MUC16), also known as Cancer Antigen 125 (CA-125), is a massive transmembrane glycoprotein that is highly overexpressed in epithelial ovarian cancers and other malignancies [1][4]. The protein consists of a large, heavily glycosylated N-terminal extracellular domain that is frequently shed into the circulation, and a C-terminal membrane-proximal region that remains anchored to the cell surface [1][5]. This membrane-proximal region (often termed MUC16-C or MUC16-CTF) is a critical therapeutic target because it is not subject to the "decoy" effect of shed CA-125, which can sequester antibodies in the serum and prevent them from reaching the tumor [2]. Biologically, MUC16 facilitates tumor cell adhesion to the peritoneum via interactions with mesothelin and contributes to immune evasion by inhibiting the activity of natural killer cells [4]. Therapeutic agents targeting the MUC16 membrane-proximal region include bispecific antibodies like ubamatamab (REGN4018) and various chimeric antigen receptor (CAR) T-cell therapies currently in clinical development [2][3]. These drugs work by redirecting the immune system to recognize the stable, membrane-bound portion of the protein, leading to targeted lysis of cancer cells. While promising, targeting MUC16 carries risks such as cytokine release syndrome (CRS) and potential on-target off-tumor toxicity due to low-level expression of MUC16 in normal tissues like the pleura and peritoneum [3][5]. Monitoring serum CA-125 levels remains a standard biomarker for disease burden, although direct immunohistochemical staining of the membrane-proximal region is increasingly used for patient selection in clinical trials [3].

Other names

CA-125Cancer antigen 125MUC16-CTFMUC16 carboxyl-terminal fragmentMUC16ectoMucin-16

T-cell redirection via bispecific antibody binding, CAR-T cell activation, and antibody-drug conjugate (ADC) internalization