6fib | pdb_00006fib
Structure of human 4-1BB ligand
Structural highlights
Function[TNFL9_HUMAN] Cytokine that binds to TNFRSF9. Induces the proliferation of activated peripheral blood T-cells. May have a role in activation-induced cell death (AICD). May play a role in cognate interactions between T-cells and B-cells/macrophages. Publication Abstract from PubMedEndogenous costimulatory molecules on T cells such as 4-1BB (CD137) can be leveraged for cancer immunotherapy. Systemic administration of agonistic anti-4-1BB antibodies, although effective preclinically, has not advanced to phase 3 trials because they have been hampered by both dependency on Fcgamma receptor-mediated hyperclustering and hepatotoxicity. To overcome these issues, we engineered proteins simultaneously targeting 4-1BB and a tumor stroma or tumor antigen: FAP-4-1BBL (RG7826) and CD19-4-1BBL. In the presence of a T cell receptor signal, they provide potent T cell costimulation strictly dependent on tumor antigen-mediated hyperclustering without systemic activation by FcgammaR binding. We could show targeting of FAP-4-1BBL to FAP-expressing tumor stroma and lymph nodes in a colorectal cancer-bearing rhesus monkey. Combination of FAP-4-1BBL with tumor antigen-targeted T cell bispecific (TCB) molecules in human tumor samples led to increased IFN-gamma and granzyme B secretion. Further, combination of FAP- or CD19-4-1BBL with CEA-TCB (RG7802) or CD20-TCB (RG6026), respectively, resulted in tumor remission in mouse models, accompanied by intratumoral accumulation of activated effector CD8(+) T cells. FAP- and CD19-4-1BBL thus represent an off-the-shelf combination immunotherapy without requiring genetic modification of effector cells for the treatment of solid and hematological malignancies. Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy.,Claus C, Ferrara C, Xu W, Sam J, Lang S, Uhlenbrock F, Albrecht R, Herter S, Schlenker R, Husser T, Diggelmann S, Challier J, Mossner E, Hosse RJ, Hofer T, Brunker P, Joseph C, Benz J, Ringler P, Stahlberg H, Lauer M, Perro M, Chen S, Kuttel C, Bhavani Mohan PL, Nicolini V, Birk MC, Ongaro A, Prince C, Gianotti R, Dugan G, Whitlow CT, Solingapuram Sai KK, Caudell DL, Burgos-Rodriguez AG, Cline JM, Hettich M, Ceppi M, Giusti AM, Crameri F, Driessen W, Morcos PN, Freimoser-Grundschober A, Levitsky V, Amann M, Grau-Richards S, von Hirschheydt T, Tournaviti S, Molhoj M, Fauti T, Heinzelmann-Schwarz V, Teichgraber V, Colombetti S, Bacac M, Zippelius A, Klein C, Umana P Sci Transl Med. 2019 Jun 12;11(496). pii: 11/496/eaav5989. doi:, 10.1126/scitranslmed.aav5989. PMID:31189721[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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