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.
Author Info: (1) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (2) ABL Bio Inc., Seongnam, Republic of
Author Info: (1) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (2) ABL Bio Inc., Seongnam, Republic of Korea. (3) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (4) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (5) ABL Bio Inc., Seongnam, Republic of Korea. (6) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (7) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (8) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (9) Department of Life Sciences, POSTECH, Pohang, Republic of Korea. (10) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (11) ABL Bio Inc., Seongnam, Republic of Korea. (12) ABL Bio Inc., Seongnam, Republic of Korea. (13) ABL Bio Inc., Seongnam, Republic of Korea. (14) ABL Bio Inc., Seongnam, Republic of Korea. (15) ABL Bio Inc., Seongnam, Republic of Korea. (16) ABL Bio Inc., Seongnam, Republic of Korea. (17) ABL Bio Inc., Seongnam, Republic of Korea. (18) ABL Bio Inc., Seongnam, Republic of Korea. (19) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (20) ABL Bio Inc., Seongnam, Republic of Korea. sw_lee@postech.ac.kr jaeho.jung@ablbio.com. (21) Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. sw_lee@postech.ac.kr jaeho.jung@ablbio.com. Department of Life Sciences, POSTECH, Pohang, Republic of Korea.
