B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8 ⁺ tumor-infiltrating lymphocytes

Abstract

Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB–dependent antitumor response in hB7-H3–overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1+Tim-3+ “terminally differentiated” subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB–expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3–positive cancers as monotherapy and combination therapy with PD-1 blockade.

B7 Family Members in Lymphoma: Promising Novel Targets for Tumor Immunotherapy?

“…B7-H3×4-1BB showed antitumor activity in mice and promoted CD8 T cell proliferation and cytokine secretion. B7-H3×4-1BB combined with PD-1 blockade synergistically suppressed tumor growth and increased terminally differentiated CD8 T cells (64). B7-H3 CAR-T cells effectively suppressed tumor growth, both in vitro and in vivo.…”

CD137 as an Attractive T Cell Co-Stimulatory Target in the TNFRSF for Immuno-Oncology Drug Development

“…Agonistic mAb to CD137 can promote NK cells to interact with CD8 + T cells and support interaction with dendritic cells (DCs) to promote their functions ( Figure 1 ) [ 14 ]. However, CD137 functionality on NK cells did not lead to direct tumor killing effects; the tumor killing is performed by CD8 + CD137 + T cells because the antitumor efficacy of a CD137-bispecific molecule in mouse studies was completely diminished in the absence of CD8 + T cells, while CD4 + T and NK cells were dispensable [ 61 ].…”

“…The urelumab dose used for this study was 8mg/kg, which was above MTD level [ 84 ]. CD137 bispecific molecules with similar potency to urelumab in combination with PD-1 blockade should be assessed in clinical trials because CD137 + TILs also express PD-1, and CD137 bispecific molecules in combination with anti-PD-1 mAb demonstrated the best synergistic effect in preclinical model systems, when compared with either CTLA-4 or TIM3 targeting molecules by enhancing terminally differentiated CD8 + T cells in tumor [ 61 ]. In addition, T cell activation via CD137 is known to increase metabolic capacity in tumor microenvironment and CD137 pretreatment is sufficient to provide metabolic support for a full anti–PD-1 response [ 85 ].…”

Bispecific Antibodies: A Smart Arsenal for Cancer Immunotherapies

“…This is composed of an Fc-silenced anti-B7-H3 mAb fused with 4-1BB-agonistic scFvs to the C-terminus of the heavy chain. B7-H3 × 4-1BB activates terminally differentiated Tim-3 + CD8 T cells in the TME and synergizes with the PD-1 blockade without inducing irAEs [ 108 ]. In addition, the novel PD-L1 × 4-1BB and Claudin18.2 × 4-1BB codeveloped by ABL Bio and I-Mab are in phase I clinical trials.…”