9F7Z

Crystal structure of human 4-1BB/TNFRSF9 in complex with the anti-4-1BB DARPin protein

Summary for 9F7Z

• Entry DOI: 10.2210/pdb9f7z/pdb
• Descriptor: anti-4-1BB DARPin, Tumor necrosis factor receptor superfamily member 9, beta-L-fucopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: tumor necrosis factor receptor superfamily member 9; 4-1bb; tnfrsf9; darpin; designed ankyrin repeat protein; immune-oncology; molecular partners ag; proteros biostructures gmbh, protein binding
• Biological source: synthetic construct; More
• Total number of polymer chains: 16
• Total formula weight: 229136.70

Authors

Malvezzi, F.,Domke, C.,Hospodarsch, T.,Lammens, A.,Blaesse, M.,Krapp, S.,Reichen, C. (deposition date: 2024-05-06, release date: 2025-05-21, Last modification date: 2026-06-03)

Primary citation

Saltarella, I.,Link, A.,Lamanuzzi, A.,Reichen, C.,Robinson, J.,Altamura, C.,Melaccio, A.,Solimando, A.G.,Ria, R.,Mariggio, M.A.,Vacca, A.,Frassanito, M.A.,Desaphy, J.F.
Improvement of daratumumab- or elotuzumab-mediated NK cell activity by the bi-specific 4-1BB agonist, DARPin alpha-FAPx4-1BB: A preclinical study in multiple myeloma.
Biomed Pharmacother, 176:116877-116877, 2024

PubMed Abstract: Multiple myeloma (MM) progression is closely dependent on cells in the bone marrow (BM) microenvironment, including fibroblasts (FBs) and immune cells. In their BM niche, MM cells adhere to FBs sustaining immune evasion, drug resistance and the undetectable endurance of tumor cells known as minimal residual disease (MRD). Here, we describe the novel bi-specific designed ankyrin repeat protein (DARPin) α-FAPx4-1BB (MP0310) with FAP-dependent 4-1BB agonistic activity. The α-FAPx4-1BB DARPin simultaneously binds to FAP and 4-1BB overexpressed by activated FBs and immune cells, respectively. Although flow cytometry analysis showed that T and NK cells from MM patients were not activated and did not express 4-1BB, stimulation with daratumumab or elotuzumab, monoclonal antibodies (mAbs) currently used for the treatment of MM, significantly upregulated 4-1BB both in vitro and in MM patients following mAb-based therapy. The mAb-induced 4-1BB overexpression allowed the engagement of α-FAPx4-1BB that acted as a bridge between FAPFBs and 4-1BBNK cells. Therefore, α-FAPx4-1BB enhanced both the adhesion of daratumumab-treated NK cells on FBs as well as their activation by improving release of CD107a and perforin, hence MM cell killing via antibody-mediated cell cytotoxicity (ADCC). Interestingly, α-FAPx4-1BB significantly potentiated daratumumab-mediated ADCC in the presence of FBs, suggesting that it may overcome the BM FBs' immunosuppressive effect. Overall, we speculate that treatment with α-FAPx4-1BB may represent a valuable strategy to improve mAb-induced NK cell activity fostering MRD negativity in MM patients through the eradication of latent MRD cells.

PubMed: 38850654
DOI: 10.1016/j.biopha.2024.116877

Experimental method

X-RAY DIFFRACTION (2.81 Å)