An anti–glypican 3/CD3 bispecific T cell–redirecting antibody for treatment of solid tumors

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.

Cancer immunotherapy‐targeted glypican‐3 or neoantigens

“…Results from this trial are eagerly awaited. In 2017, the results of fundamental research about ERY974, an anti‐GPC3/CD3 bispecific T cell‐redirecting antibody, were reported . We would like to expect future clinical applications of this novel drug.…”

Bispecific antibodies enhance tumor-infiltrating T cell cytotoxicity against autologous HER-2-expressing high-grade ovarian tumors

“…Commonly, HER‐2 expression is detected in 22–66% of ovarian cancer patients . New therapeutic strategies such as the development of bispecific antibodies (bsAbs) with the aim to achieve more effective and durable response, are of major clinical interest . The bsAbs enhance cytotoxic activity by selectively targeting immune cells to tumor‐associated antigens such as HER‐2 .…”

ImmunoPET as Stoichiometric Sensor for Glypican-3 in Models of Hepatocellular Carcinoma

“…Since only about half of HCCs take up 18 FDG PET, the standard functional tracer, immunoPET may serve as an informative imaging biomarker in such circumstances and could allow more timely local or systemic interventions (5). GPC3 is a known marker of HCC and several GPC3-directed agents, including vaccines, monoclonal antibodies, bispecific T-cell engagers, single-domain antibody conjugates, targeted peptides, and chimeric antigen receptor T-cells (26,28,30,(35)(36)(37)(38)(39). Accordingly, identifying tumors that express GPC3 with immunoPET could help better enrich for populations that may most benefit from these treatments (32).…”