7P3I

Crystal structure of human CD40/TNFRSF5 in complex with the anti-CD40 DARPin protein

Summary for 7P3I

• Entry DOI: 10.2210/pdb7p3i/pdb
• Descriptor: Tumor necrosis factor receptor superfamily member 5, Darpin, SODIUM ION, ... (4 entities in total)
• Functional Keywords: tnfrsf5, immune-oncology, cd40, unknown function
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 72840.05

Authors

Malvezzi, F.,Mangold, S.,Hospodarsch, T.,Reichen, C.,Iss, C.,Lammens, A.,Krapp, S.,Domke, C. (deposition date: 2021-07-07, release date: 2022-04-06, Last modification date: 2024-11-13)

Primary citation

Rigamonti, N.,Veitonmaki, N.,Domke, C.,Barsin, S.,Jetzer, S.,Abdelmotaleb, O.,Bessey, R.,Lekishvili, T.,Malvezzi, F.,Gachechiladze, M.,Behe, M.,Levitsky, V.,Trail, P.A.
A Multispecific Anti-CD40 DARPin Construct Induces Tumor-Selective CD40 Activation and Tumor Regression.
Cancer Immunol Res, 10:626-640, 2022

PubMed Abstract: The CD40 receptor is an attractive target for cancer immunotherapy. Although a modest pharmacodynamic effect is seen in patients following administration of CD40-targeting monoclonal antibodies (mAb), the doses that could be safely administered do not result in a meaningful clinical response, most likely due to the limited therapeutic window associated with systemic CD40 activation. To overcome this issue, we developed a multispecific DARPin construct, α-FAPxCD40, which has conditional activity at the site of disease. α-FAPxCD40 activation of CD40 depends on binding to fibroblast activation protein (FAP), a cell-surface protease overexpressed in the stroma of solid tumors. In vitro studies demonstrated that α-FAPxCD40 potently activates human antigen-presenting cells in the presence, but not in the absence, of FAP-positive cells. After intravenous injection, a murine surrogate construct (α-mFAPxCD40) accumulated in FAP-positive tumors, elicited rejection of 88% of these tumors, and induced memory antitumor immunity. Importantly, in contrast to the mouse anti-CD40 tested in parallel, the in vivo antitumor activity of α-mFAPxCD40 was associated neither with elevated blood cytokines nor with hepatotoxicity, both of which contribute to the clinical dose-limiting toxicities of several CD40 mAb. This study demonstrates that α-(m)FAPxCD40 engages CD40 in an FAP-restricted manner, leading to tumor eradication without signs of peripheral toxicity. This distinct preclinical profile suggests that a favorable therapeutic index may be achieved in humans. It further supports the development of α-FAPxCD40, currently tested in a first-in-human clinical study in patients with solid tumors (NCT05098405).

PubMed: 35319751
DOI: 10.1158/2326-6066.CIR-21-0553

Experimental method

X-RAY DIFFRACTION (2.29 Å)