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Tumor-targeted 4-1BB Agonists for Combination With T Cell Bispecific Antibodies as Off-The-Shelf Therapy

Tumor-targeted 4-1BB Agonists for Combination With T Cell Bispecific Antibodies as Off-The-Shelf Therapy

Christina Claus, Claudia Ferrara, Wei Xu, Johannes Sam, Sabine Lang, Franziska Uhlenbrock, Rosmarie Albrecht, Sylvia Herter, Ramona Schlenker, Tamara Hüsser, Sarah Diggelmann, John Challier, Ekkehard Mössner, etc.

Sci Transl Med. 2019 Jun 12;11(496):eaav5989.

PMID: 31189721

Abstract:

Endogenous 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 Fcγ 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 FcγR 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-γ 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4248874	4-1BBL human			Price

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