An IgG‐based bispecific antibody for improved dual targeting in PSMA‐positive cancer. Issue 2 (29th December 2020) - Zekri, Latifa
Abstract: The prostate‐specific membrane antigen (PSMA) has been demonstrated in numerous studies to be expressed specifically on prostate carcinoma cells and on the neovasculature of several other cancer entities. However, the simultaneous expression of PSMA on both, tumor cells as well as tumor vessels remains unclear, even if such "dual" expression would constitute an important asset to facilitate sufficient influx of effector cells to a given tumor site. We report here on the generation of a PSMA antibody, termed 10B3, which exerts superior dual reactivity on sections of prostate carcinoma and squamous cell carcinoma of the lung. 10B3 was used for the construction of T‐cell recruiting bispecific PSMAxCD3 antibodies in Fab‐ and IgG‐based formats, designated Fabsc and IgGsc, respectively. In vitro, both molecules exhibited comparable activity. In contrast, only the larger IgGsc molecule induced complete and durable elimination of established tumors in humanized mice due to favorable pharmacokinetic properties. Upon treatment of three patients with metastasized prostate carcinoma with the IgGsc reagent, marked activation of T cells and rapid reduction of elevated PSA levels were observed. Synopsis: Insufficient penetration of immune cells and therapeutic antibodies into the tumor core is a major limitation in the immunotherapy field. This study reports the development of a novel bispecific antibody, named CC‐1, for improved dual targeting of tumor‐ and vascular cells in PSMA positive tumors. A novel PSMA antibody (10B3) exhibiting enhanced reactivity with tumor‐ and vascular cells in samples from prostate carcinoma and squamous cell carcinoma of the lung was generated. Two different bispecific antibodies comprising 10B3 and anti‐CD3 single chain in a Fabsc‐ and IgGsc‐format were constructed and characterized. In vivo application of both bispecific antibodies revealed that only the IgGsc‐molecule localized at a given tumor site, resulting in effective tumor cell destruction. A first‐in‐man application of the IgGsc‐molecule, designated CC‐1, in three patients with metastasized prostate carcinoma, demonstrated profound T cell activation and a rapid decline of elevated PSA levels. A first‐in‐man clinical study in patients with prostate carcinoma is currently ongoing (NCT04104607). Abstract : Insufficient penetration of immune cells and therapeutic antibodies into the tumor core is a major limitation in the immunotherapy field. This study reports the development of a novel bispecific antibody, named CC‐1, for improved dual targeting of tumor‐ and vascular cells in PSMA positive tumors.