B7-H3x4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8+ tumor-infiltrating lymphocytes

Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3x4-1 BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3xm4-1BB 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-H3xh4-1BB also shows antitumor activity in h4-1 BB-expressing mice. Our data suggest that B7-H3x4-1 BB is an effective and safe therapeutic agent against B7-H3-positive cancers as monotherapy and combination therapy with PD-1 blockade.

Automated summary

The bispecific antibody B7-H3x4-1BB effectively restricts 4-1BB stimulation in tumors and elicits a 4-1BB-dependent antitumor response, primarily targeting CD8 T cells for increased proliferation and cytokine production. Combination therapy with PD-1 blockade further enhances this antitumor activity by increasing terminally differentiated CD8 T cells, providing an effective and safe treatment option for B7-H3-positive cancers.