Abstract
Therapeutic monoclonal antibodies (mAbs) blocking immune checkpoints have been mainly used as monotherapy. Recently, combination therapy targeting multiple immune checkpoints has recently been explored to increase anti-cancer efficacy. Particularly, a single molecule targeting more than one checkpoints has been investigated. As dual blocking of PD-1/PD-L1 and VEGF/VEGFR has demonstrated synergism in anti-tumor activities, we developed a novel bispecific antibody, termed HB0025, which is formed via fusing the domain 2 of vascular endothelial growth factor receptor 1 (VEGFR1D2) and anti-PD-L1 mAb by using mAb-Trap technology. HB0025 almost completely retains the binding affinities and the biological activities in-vitro when compared with the parent anti-PD-L1 mAb or VEGFR1D2 fusion protein. Preclinical data demonstrated that HB0025 was more effective in inhibiting cancer growth than anti PD-L1 mAb or VEGFR1D2 fusion protein. Thus, our bispecific antibody may bring about greater clinical benefits and broader indications.
Highlights
As the second leading cause of human death globally, malignancies remain a major public health issue [1]
A375 human melanoma cell line was obtained from the American Type Culture Collection (ATCC, USA) and was maintained in vitro as monolayer culture in DMEM medium supplemented with 10% heat inactivated fetal calf serum, 100 U/ ml penicillin and 100mg/ml streptomycin; human umbilical vein endothelial cells (HUVEC) were obtained from ATCC; peripheral blood mononuclear cells (PBMCs) used in humanized mice were obtained from SAILYBIO (Shanghai, China); PBMCs used in the mixed lymphoid reaction (MLR) and dendritic cells (DCs) were purchased from Allcells (PCH2019000001, California, USA); CHO-K1-OS8-programmed cell death-ligand 1 (PD-L1)-8D6 cells and Jurkat-NFAT-PD-1-5B8 cells were generated in-house
To generate the bispecific antibody HB0025, the soluble extracellular domain 2 of VEGFR1D2 was fused to the N-terminus of the heavy chain of HB0023 via a (G2S)5 linker
Summary
As the second leading cause of human death globally, malignancies remain a major public health issue [1]. The mAbs targeting programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) can reactivate suppressed T-cells to block the cancer-immune escape [6]. PD-1 is composed of one immunoglobulin superfamily domain, a 20-amino acid stalk, a transmembrane domain, and a 95residue intracellular domain [7]. It is mainly expressed in activated T-cells, B-cells, natural killer cells, monocytes, and mesenchymal stem cells [8]. PD-1 ligand is a 290-amino acid type I transmembrane cell surface glycoprotein encoded by Cd274 on mouse chromosome 19 and human chromosome 9 [9]. PD-L1 has been found to be expressed by many types of tumor cells [11]
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