You and Lee et al. tested a bispecific antibody (bsAb) that contains a mouse 4-1BB agonist and targets the inhibitory receptor B7-H3, which is expressed by multiple tumor types while absent from healthy tissues. The bsAb induced antitumor activity, which was more evident in immunogenic tumor models (MC38 & CT26). The bsAb induced infiltration of terminally differentiated PD-1+Tim3+CD8+ T cells, and anti-PD-1 acted in synergy by also inducing differentiation of stem-like CD8+ T cells. No synergy was observed with anti-CTLA4 or anti-Tim3. A bispecific targeting human 4-1BB behaved similarly, warranting human testing.
Contributed by Maartje Wouters
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.