Anti-CDH3/P-cadherin Antibody(

FF-21101 is a human IgG1 monoclonal antibody (mAb) targeting CDH3/P-cadherin。A radioimmunoconjugate consisting of a chimeric monoclonal antibody targeting human cadherin-3 (CDH3) and labeled, via the macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), with the beta-emitting radioisotope yttrium Y 90, with potential antineoplastic activities. Upon administration, the antibody moiety of yttrium Y 90 anti-CDH3 monoclonal antibody FF-21101 binds to CDH3 expressed on tumor cells, thereby specifically delivering cytotoxic beta radiation to CDH3-expressing tumor cells. CDH3, also known as P-cadherin, is a tumor-associated antigen (TAA) and member of the cadherin family; it is overexpressed in a variety of tumors and plays a role in cell adhesion, motility, invasion, and proliferation.

P-cadherin is overexpressed in various cancers and can be a target for radioimmunotherapy. We investigated the preclinical pharmacokinetics and pharmacology of FF-21101, an indium-111 (111In)- or yttrium-90 (90Y)-conjugated monoclonal antibody against P-cadherin, to evaluate its clinical applications. Methods: The radiochemical purity, binding affinity, and in vitro serum stability of 111In/90Y-labeled FF-21101 were evaluated. The pharmacokinetics of 111In/90Y-FF-21101 were compared in normal mice. Tumor accumulation after 111In-FF-21101 administration was investigated in mice bearing subcutaneous tumors with high (NCI-H1373), moderate (EBC-1), and negative (A549) P-cadherin expression. The tumor suppression effect following a single intravenous injection of 90Y-FF-21101 was assessed in NCI-H1373 and EBC-1 mouse xenograft models. The relationship between antibody dose and tumor accumulation was investigated in the NCI-H1373 mouse xenograft model. The radiation-absorbed dose in humans after injection of 90Y-FF-21101 was estimated using gamma camera images of cynomolgus monkeys.

Signaling pathways participating in the function of cadherins in cancer. (A) E-cadherin loss lead to the upregulation of β-catenin in cytoplasm. After Wnt binds to Frizzled, it blocks the effects of CK1α and GSK3 on β-catenin and cause the accumulation of β-catenin in cytoplasm and nucleus, which activates TCF/LEF and co-activators. N-cadherin could affect tumorigenesis through interacting with FGFR and stimulating MAPK/ERK pathway. (B) Wnt-β-catenin pathway also works in tumor progression like in (A). E-cadherin could also activate PI3K-AKT and MEK-ERK pathways. N-cadherin activates Ras-MAPK pathway, TCF/LEF transcription factor, etc. P-cadherin could increase tumor migration through interacting with integrin. (C) In endothelial cells, VEGF-VEGFR2 activates VE-cadherin and Src, then leads to VE-cadherin phosphorylation on tyrosines, which would promote endothelial cell proliferation through PI3K/AKT signaling. ERK/MAPK signaling pathway would be stimulated without tyrosines phosphorylation. sN-cadherin induces by proteases could bind to FGFR and phosphorylates ERK to stimulate angiogenesis. (D) The Wnt-β-catenin signaling pathway also works in immune cells, which stimulates anti-inflammatory macrophages and tolerogenic DCs. E-cadherin mediates anti-inflammatory activation of macrophages and DCs through PI3K/AKT and NF-κB. FGFR, fibroblast growth factor receptor; DVL, disheveled protein; P, phosphorylation; APC, adenomatosis polyposis coli; MAPK, mitogen-activated protein-kinase; ERK, extracellular signal-regulated kinase; GSK3, glycogen synthase kinase; BCL9, B-cell lymphoma 9; TCF/LEF, T-cell factor/lymphoid enhancer factor; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; CBP, CREB-binding protein; HAV, His–Ala–Val; VEGF, vascular endothelial growth factor; VEGF-R2, vascular endothelial growth factor receptor 2; P-Y, phosphorylation on tyrosin; PTEN, gene of phosphate and tension homology deleted on chromsome ten; NF-κB, nuclear factor κB; CK1α, casein kinase 1 α; TGF-β, Transforming growth factor beta.