8GH4

Complex of Adam 10 disentegrin cysteine rich domains with human monoclonal antibody

Summary for 8GH4

• Entry DOI: 10.2210/pdb8gh4/pdb
• Descriptor: Antibody heavy chain, Antibody light chain, Disintegrin and metalloproteinase domain-containing protein 10, ... (4 entities in total)
• Functional Keywords: colorectal cancer, adam 10, human monoclonal antibody, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 68906.23

Authors

Nikolov, D.B.,Saha, N.,Xu, K.,Goldgur, Y. (deposition date: 2023-03-09, release date: 2023-08-30, Last modification date: 2024-11-20)

Primary citation

Saha, N.,Baek, D.S.,Mendoza, R.P.,Robev, D.,Xu, Y.,Goldgur, Y.,De La Cruz, M.J.,de Stanchina, E.,Janes, P.W.,Xu, K.,Dimitrov, D.S.,Nikolov, D.B.
Fully human monoclonal antibody targeting activated ADAM10 on colorectal cancer cells.
Biomed Pharmacother, 161:114494-114494, 2023

PubMed Abstract: Metastasis and chemoresistance in colorectal cancer are mediated by certain poorly differentiated cancer cells, known as cancer stem cells, that are maintained by Notch downstream signaling initiated upon Notch cleavage by the metalloprotease ADAM10. It has been shown that ADAM10 overexpression correlates with aberrant signaling from Notch, erbBs, and other receptors, as well as a more aggressive metastatic phenotype, in a range of cancers including colon, gastric, prostate, breast, ovarian, uterine, and leukemia. ADAM10 inhibition, therefore, stands out as an important and new approach to deter the progression of advanced CRC. For targeting the ADAM10 substrate-binding region, which is located outside of the catalytic domain of the protease, we generated a human anti-ADAM10 monoclonal antibody named 1H5. Structural and functional characterization of 1H5 reveals that it binds to the substrate-binding cysteine-rich domain and recognizes an activated ADAM10 conformation present on tumor cells. The mAb inhibits Notch cleavage and proliferation of colon cancer cell lines in vitro and in mouse models. Consistent with its binding to activated ADAM10, the mAb augments the catalytic activity of ADAM10 towards small peptide substrates in vitro. Most importantly, in a mouse model of colon cancer, when administered in combination with the therapeutic agent Irinotecan, 1H5 causes highly effective tumor growth inhibition without any discernible toxicity effects. Our singular approach to target the ADAM10 substrate-binding region with therapeutic antibodies could overcome the shortcomings of previous intervention strategies of targeting the protease active site with small molecule inhibitors that exhibit musculoskeletal toxicity.

PubMed: 36917886
DOI: 10.1016/j.biopha.2023.114494

Experimental method

X-RAY DIFFRACTION (3.8 Å)