Research ArticleCancer

Tumor-targeted 4-1BB agonists for combination with T cell bispecific antibodies as off-the-shelf therapy

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Science Translational Medicine  12 Jun 2019:
Vol. 11, Issue 496, eaav5989
DOI: 10.1126/scitranslmed.aav5989

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For the love of 4-1BB

Antibodies activating the 4-1BB costimulatory molecule did not succeed as cancer immunotherapy due to adverse events in patients. Claus et al. have now taken a protein engineering approach to make a next-generation 4-1BB agonist. They generated constructs with a trimeric 4-1BBL portion that engages 4-1BB on T cells without harmful Fc receptor cross-linking. The constructs also include tumor antigen–targeting portions and can be used in conjunction with other immunotherapies. These proteins successfully stimulated T cells in explanted samples from patients with cancer and improved survival in multiple mouse models. This approach reveals a potentially better way to stimulate 4-1BB for cancer immunotherapy.


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.

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