Anti-Human HER3 antibody (Bare

Barecetamab (ISU-104) 是一种人源化抗酪氨酸蛋白激酶 ErbB3 的单克隆抗体，具有抗癌活性，可用于研究期恶性实体瘤。

Barecetamab (ISU-104) is a humanized monoclonal antibody against tyrosine protein kinase ErbB3 with anticancer activity for use in investigational stage malignant solid tumors.barecetamab A fully human antibody directed against the receptor tyrosine-protein kinase erbB-3 (ErbB3; HER3) with potential antineoplastic activity. Upon intravenous administration, barecetamab targets and binds to domain 3 and weakly interacts with domain 1 of ErbB3. This prevents heregulin (HRG) binding and blocks dimerization of ErbB3, thereby inactivating ErbB3 downstream signaling. ISU104 may also elicit the internalization of ErbB3 from the plasma membrane and downregulate ErbB3 expression. This inhibits cellular proliferation and survival of ErbB3-expressing tumor cells. ErbB3, a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, is frequently overexpressed in a variety of tumors and its overexpression generally correlates with poor prognosis and tumor resistance.

HER3 is a unique EGFR family member with no or little intracellular tyrosine kinase activity. Compared with the other EGFR family members, HER3 diverges at critical residues in the kinase domain locking it in an inactive-like conformation . Although HER3 has been reported to have some kinase activity, it is suggested to be 1000-fold weaker than the kinase activity of the fully activated EGFR . Since HER3 is unable to form homodimers, its activation depends on heterodimerization with another receptor in order to induce the downstream C-terminal phosphorylation events .

The HER3 gene localizes in the long arm of chromosome 12 (12q13.2), encoding a 180 kDa protein . The extracellular domain of HER3 is divided into four subdomains (I–IV): subdomains I and III are leucine-rich β-helical areas responsible for the ligand binding, whereas subdomains II and IV are cysteine-rich regions. Subdomain II also contains a dimerization arm necessary for the interaction with other receptors. The transmembrane domain is followed by an intracellular domain enclosing a flexible juxtamembrane region, kinase domain, and the C-terminal tail. In absence of a ligand, binding between subdomains II and IV keeps HER3 in an inactive state . Upon ligand binding, the dimerization partner’s kinase domain trans-phosphorylates the tyrosine residues in the C-terminal tail of HER3 .

Upon ligand binding, HER3 preferentially dimerizes with EGFR or HER2 inducing a conformational change in the receptor pair. The conformational change leads into transphosphorylation event in the intracellular kinase tail, where the C-terminal tail of HER3 acts as an acceptor for multiple phosphorylations. This induces activation of signaling cascades promoting cell survival and proliferation. EGFR: Epidermal growth factor receptor, EGF: Epidermal growth factor, HER2: Human epidermal growth factor receptor 2, HER3: Human epidermal growth factor receptor 3, NRG: Neuregulin, p85: 85kDa regulator subunit of phosphoinositide 3-kinase, p110: 110kDa catalytic subunit of phosphoinositide 3-kinase, AKT: protein kinase B, SHC: SHC-transforming protein 1, GRB2: growth factor receptor bound protein 2, SOS: Son of sevenless, RAS: RAS GTPase, RAF: Raf kinase, MAPK: Mitogen-activated protein kinase.

HER3 is a unique EGFR family member with no or little intracellular tyrosine kinase activity. Compared with the other EGFR family members, HER3 diverges at critical residues in the kinase domain locking it in an inactive-like conformation . Although HER3 has been reported to have some kinase activity, it is suggested to be 1000-fold weaker than the kinase activity of the fully activated EGFR . Since HER3 is unable to form homodimers, its activation depends on heterodimerization with another receptor in order to induce the downstream C-terminal phosphorylation events .

The HER3 gene localizes in the long arm of chromosome 12 (12q13.2), encoding a 180 kDa protein . The extracellular domain of HER3 is divided into four subdomains (I–IV): subdomains I and III are leucine-rich β-helical areas responsible for the ligand binding, whereas subdomains II and IV are cysteine-rich regions. Subdomain II also contains a dimerization arm necessary for the interaction with other receptors. The transmembrane domain is followed by an intracellular domain enclosing a flexible juxtamembrane region, kinase domain, and the C-terminal tail. In absence of a ligand, binding between subdomains II and IV keeps HER3 in an inactive state . Upon ligand binding, the dimerization partner’s kinase domain trans-phosphorylates the tyrosine residues in the C-terminal tail of HER3 .

Upon ligand binding, HER3 preferentially dimerizes with EGFR or HER2 inducing a conformational change in the receptor pair. The conformational change leads into transphosphorylation event in the intracellular kinase tail, where the C-terminal tail of HER3 acts as an acceptor for multiple phosphorylations. This induces activation of signaling cascades promoting cell survival and proliferation. EGFR: Epidermal growth factor receptor, EGF: Epidermal growth factor, HER2: Human epidermal growth factor receptor 2, HER3: Human epidermal growth factor receptor 3, NRG: Neuregulin, p85: 85kDa regulator subunit of phosphoinositide 3-kinase, p110: 110kDa catalytic subunit of phosphoinositide 3-kinase, AKT: protein kinase B, SHC: SHC-transforming protein 1, GRB2: growth factor receptor bound protein 2, SOS: Son of sevenless, RAS: RAS GTPase, RAF: Raf kinase, MAPK: Mitogen-activated protein kinase.