Targeting Multiple Receptors: The Advancement of a Trispecific Antibody in Small Cell Lung Cancer Therapy

A novel single domain VHH multi-specific antibody structure has been engineered, with potential to address significant medical needs in cancers such as small cell lung cancer (SCLC). This trispecific antibody, designated KB-436, is designed to target three distinct receptors: Dopamine Receptor 2 (DRD2), PD-1, and CD47. DRD2, a receptor linked to poor patient outcomes and increased cancer cell stemness, is prevalent in many cancers including SCLC, where it is highly expressed in a majority of patients. The PD-1 pathway has been a focus of lung cancer treatment, with PD-L1 inhibitors approved for first-line therapy. However, SCLC patients often face rapid chemotherapy failure and resistance to immunotherapy, which may be associated with low levels of immune cell infiltration and high levels of circulating tumor cells.

The trispecific antibody KB-436 is composed of three VHH modules targeting DRD2, PD-1, and CD47, each contributing to a multifaceted anti-tumor effect. The anti-DRD2 module triggers intracellular signaling, the anti-PD-1 module enhances T cell function, and the anti-CD47 module facilitates T cell recruitment and inhibits the CD47-SIRPa interaction. In preclinical studies, KB-436 demonstrated significant tumor growth suppression in a DRD2-positive SCLC model and showed robust anti-tumor efficacy across various xenograft models of human SCLC and solid tumors. The treatment not only suppressed tumor growth but also enhanced the effects of cisplatin, blocked metastasis formation, and increased survival in metastatic models.

KB-436 exhibits a half-life of approximately 5 days in mice, is produced at a high yield, and has shown high purity and stability. These characteristics, along with its strong in vivo anti-tumor activity, support the advancement of KB-436 into clinical development for the treatment of advanced metastatic solid cancers, including SCLC.

The research was presented by Shugang Yao et al. at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics in October 2021, with the abstract published in the Molecular Cancer Therapeutics journal.