9W6S

hCA450-21.1 Fab and GD2 complex

Summary for 9W6S

• Entry DOI: 10.2210/pdb9w6s/pdb
• Descriptor: Light chain of GD2 antibody hCA450-21.1 Fab, Heavy chain of GD2 antibody hCA450-21.1 Fab, N-acetyl-alpha-neuraminic acid-(2-8)-N-acetyl-alpha-neuraminic acid-(2-3)-[2-acetamido-2-deoxy-beta-D-galactopyranose-(1-4)]beta-D-galactopyranose-(1-4)-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: ganglioside gd2, gd2 antibody, complex, recombination
• Biological source: Mus musculus; More
• Total number of polymer chains: 4
• Total formula weight: 96045.41

Authors

Deyong, S.,Muding, R. (deposition date: 2025-08-05, release date: 2026-06-17, Last modification date: 2026-07-15)

Primary citation

Song, D.,Han, J.,Dong, C.,Wang, Q.,Zhu, X.,Li, J.,Rao, M.,Liu, H.,Ma, Z.,Teng, Y.,Dou, C.,Xiao, M.
Identification and Preclinical Evaluation of a Novel GD2 Antibody-Drug Conjugate for Solid Tumors in Children and Adults.
Mol.Cancer Ther., 25:1037-1048, 2026

PubMed Abstract: The ganglioside GD2 is an attractive cancer target due to its high expression in neuroblastoma and other solid tumors, with limited normal tissues distribution. Despite regulatory approvals of three anti-GD2 antibodies, clinical efficacy remains limited by neurotoxicity, suboptimal affinity for ADCC, and immunogenicity. Developing a highly effective, less toxic anti-GD2 agent remains an unmet need. In this study, a novel anti-GD2 murine antibody, CA450, was identified by immunizing mice with GD2 conjugated to KLH or Qβ virus-like particles (VLP), followed by phage display screening. The humanized version, hCA450-21, displayed higher cell-binding activity than ch14.18 and Hu3F8, along with excellent specificity and internalization capacity. To overcome the limitations of traditional anti-GD2 antibody therapy, hCA450-21 was engineered and conjugated to Exatecan to create an antibody-drug conjugate (ADC), which may reduce or avoid neurotoxicity by employing a mechanism distinct from antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). The hCA450-21.1-LA-68B ADC demonstrated potent in vitro cytotoxicity against glioblastoma, melanoma, and breast cancer cell lines, and in vivo tumor growth inhibition in LN229 and SK-MEL-5 xenograft models. Toxicity studies in mice showed a favorable safety profile, with reduced neurotoxicity compared to naked antibody therapy by ch14.18-IgG1 and hCA450-21.1-IgG1. The crystal structure of the hCA450-21.1 Fab-GD2 complex was resolved at 1.69 Å, revealing unique hydrogen bonds and hydrophobic interactions that contribute to its high specificity and affinity. Overall, the novel hCA450-21.1-LA-68B ADC shows preclinical efficacy and reduced toxicity, particularly neurotoxicity, indicating potential as a safer and more effective therapy for GD2-positive pediatric and adult tumors.

PubMed: 41609209
DOI: 10.1158/1535-7163.MCT-25-0728

Experimental method

X-RAY DIFFRACTION (1.69 Å)