A novel 4-1BB/HER2 bispecific antibody shows potent antitumor activities by increasing and activating tumor-infiltrating T cells

Aolin Shen; Wenting Liu; Huizhen Wang; Xiaoli Zeng; Mengli Wang; Dayan Zhang; Qun Zhao; Qing Fang; Fengrong Wang; Liansheng Cheng; Guodong Shen; Yongxiang Li

A novel 4-1BB/HER2 bispecific antibody shows potent antitumor activities by increasing and activating tumor-infiltrating T cells

Am J Cancer Res. 2023 Jul 15;13(7):3246-3256. eCollection 2023.

Authors

Aolin Shen^{1

2}, Wenting Liu³, Huizhen Wang¹, Xiaoli Zeng³, Mengli Wang³, Dayan Zhang³, Qun Zhao³, Qing Fang³, Fengrong Wang³, Liansheng Cheng^{2

3

4}, Guodong Shen^{2

5}, Yongxiang Li¹

Affiliations

¹ Department of General Surgery, The First Affiliated Hospital of Anhui Medical University Hefei 230032, Anhui, China.
² Anhui Provincial Key Laboratory of Tumor Immunotherapy and Nutrition Therapy Hefei 230001, Anhui, China.
³ Hefei HankeMab Biotechnology Co., Ltd. Hefei 230088, Anhui, China.
⁴ Anhui Province Key Laboratory of Gene Engineering Pharmaceutical, Biomedicine Technology Innovation Center of Hefei, Anhui Anke Biotechnology (Group) Co., Ltd. Hefei 230088, Anhui, China.
⁵ Department of Geriatrics, The First Affiliated Hospital of University of Science and Technology of China, Gerontology Institute of Anhui Province, Division of Life Sciences and Medicine, University of Science and Technology of China Hefei 230001, Anhui, China.

PMID: 37559991
PMCID: PMC10408481

Abstract

Resistance to HER2-targeted therapy narrows the efficacy of cancer immunotherapy. Although 4-1BB/CD137 is a promising drug target as a costimulatory molecule of immune cells, no therapeutic drug has been approved in the clinic because of systemic toxicity or limited efficacy. Previously, we developed a humanized anti-HER2 monoclonal antibody (mAb) HuA21 and anti-4-1BB mAb HuB6 with distinct antigen epitopes for cancer therapy. Here, we generated an Fc-muted IgG4 HER2/4-1BB bispecific antibody (BsAb) HK006 by the fusion of HuB6 scFv and HuA21 Fab. HK006 exhibited synergistic antitumor activity by blocking HER2 signal transduction and stimulating the 4-1BB signaling pathway simultaneously and strictly dependent on HER2 expression in vitro and in vivo. Strikingly, HK006 treatment enhanced antitumor immunity by increasing and activating tumor-infiltrating T cells. Moreover, HK006 did not induce nonspecific production of proinflammatory cytokines and had no obvious toxicity in mice. Overall, these data demonstrated that HK006 should be a promising candidate for HER2-positive cancer immunotherapy.

Keywords: 4-1BB/CD137; Cancer immunotherapy; HER2; antitumor immunity; monoclonal antibody.