Abstract 2865: CC-3, an IgG-based B7-H3xCD3 bispecific antibody for targeting of gastrointestinal cancers

Abstract

Abstract Despite substantial improvements over the last decades, survival rates in metastatic gastrointestinal cancer are still far from satisfactory, with an accordingly high medical need for new treatment strategies. B7-H3 (CD276) is a member of the B7 immune checkpoint family. Initially thought to act as co-stimulator, recent studies revealed that B7-H3 rather has an inhibitory role for T cells and contributes to tumor immune evasion. Clinically, its overexpression has been linked to invasive and metastatic potential as well as poor prognosis. Due to its expression on both, tumor cells and tumor vasculature, in a variety of cancer entities including colorectal cancer, B7-H3 attracted our interest as therapeutic target for T cell-recruiting bispecific antibodies (bsAbs). We postulate that “dual targeting” of both, the cancer cells and the tumor vasculature may support the influx of T cells into the tumor site, a critical prerequisite for successful immunotherapy of solid tumors allowing for subsequent destruction of antigen-positive malignant cells. We generated a panel of monoclonal antibodies directed to different epitopes of the B7-H3 molecule. After biochemical characterization, we selected two antibodies with distinct binding proprieties and subsequently used them for the construction of Tcell-recruiting B7-H3xCD3 bsAbs in an IgG-based (IgGsc) format. To reduce side effects, constructs were cloned using a UCHT-1 derived low affinity anti-CD3 sequence. In vitro characterization using colorectal and other carcinoma cells allowed for selection of a construct with optimal functional properties (thereafter termed CC-3) as revealed by target cell-restricted induction of T cell activation, proliferation and tumor cell killing. In vivo, potent efficacy of CC-3 was documented in a lung metastasis model and by its ability to eliminate large established flank tumors using immunocompromised NSG mice adoptively transferred with human effector cells. Despite the high therapeutic efficacy of CC-3, no toxicity was observed in the absence of target cells. In summary, CC-3 is a bsAb with promising therapeutic activity against B7-H3 positive tumors. GMP compliant production of CC-3 is presently ongoing to enable evaluation in a clinical “first in human” study in patients with colorectal cancer. Citation Format: Latifa Zekri, Martina S. Lutz, Ilona Hagelstein, Timo Manz, Monika Engel, Boris Klimovich, Nisha Prakash, Anna Chashchina, Sebastian Hörner, Stefanie Müller, Melanie Märklin, Martin Pflügler, Gundram Jung, Helmut R. Salih. CC-3, an IgG-based B7-H3xCD3 bispecific antibody for targeting of gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2865.