1. An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors
- Author
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Tomoyuki Igawa, Hiroko Konishi, Shuichi Chiba, Yukari Nishito, Etsuko Fujii, Hiroaki Segawa, Toshiaki Tsunenari, Atsushi Narita, Asako Harada, Takashi Tsushima, Hirotake Shiraiwa, Kunihiro Hattori, Eitaro Nanba, Ehab Elgabry, Akihisa Kaneko, Mizuho Noguchi, Lorraine Stewart, Masahiro Aoki, Mika Endo, Hironori Mutoh, Yuji Sano, Jun-ichi Nezu, Yukiko Sonobe, Yoshiki Kawabe, Yumiko Azuma, Shun-ichiro Komatsu, Tetsuya Wakabayashi, Akihisa Sakamoto, Natsuki Ono, Yoko Kayukawa, Kiyoaki Sakata, Yasuko Kinoshita, Yoko Miyazaki, Toshihiko Fujii, Masaki Ishigai, Mika Kamata-Sakurai, Mina Takahashi, Takahiro Ishiguro, and Werner Frings
- Subjects
0301 basic medicine ,CD3 Complex ,medicine.medical_treatment ,T cell ,T-Lymphocytes ,Antineoplastic Agents ,Mice, Transgenic ,Biology ,Lymphocyte Activation ,CD19 ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Glypicans ,Neoplasms ,Antibodies, Bispecific ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Tumor microenvironment ,General Medicine ,Immunotherapy ,Macaca fascicularis ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Injections, Intravenous ,biology.protein ,Cytokines ,Steroids ,Antibody ,Immunocompetence - Abstract
Cancer care is being revolutionized by immunotherapies such as immune checkpoint inhibitors, engineered T cell transfer, and cell vaccines. The bispecific T cell-redirecting antibody (TRAB) is one such promising immunotherapy, which can redirect T cells to tumor cells by engaging CD3 on a T cell and an antigen on a tumor cell. Because T cells can be redirected to tumor cells regardless of the specificity of T cell receptors, TRAB is considered efficacious for less immunogenic tumors lacking enough neoantigens. Its clinical efficacy has been exemplified by blinatumomab, a bispecific T cell engager targeting CD19 and CD3, which has shown marked clinical responses against hematological malignancies. However, the success of TRAB in solid tumors has been hampered by the lack of a target molecule with sufficient tumor selectivity to avoid "on-target off-tumor" toxicity. Glypican 3 (GPC3) is a highly tumor-specific antigen that is expressed during fetal development but is strictly suppressed in normal adult tissues. We developed ERY974, a whole humanized immunoglobulin G-structured TRAB harboring a common light chain, which bispecifically binds to GPC3 and CD3. Using a mouse model with reconstituted human immune cells, we revealed that ERY974 is highly effective in killing various types of tumors that have GPC3 expression comparable to that in clinical tumors. ERY974 also induced a robust antitumor efficacy even against tumors with nonimmunogenic features, which are difficult to treat by inhibiting immune checkpoints such as PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T lymphocyte-associated protein-4). Immune monitoring revealed that ERY974 converted the poorly inflamed tumor microenvironment to a highly inflamed microenvironment. Toxicology studies in cynomolgus monkeys showed transient cytokine elevation, but this was manageable and reversible. No organ toxicity was evident. These data provide a rationale for clinical testing of ERY974 for the treatment of patients with GPC3-positive solid tumors.
- Published
- 2016