Lbl-034, a Highly Differentiated T-Cell Engaging Bispecific Antibody Targeting GPRC5D for the Treatment of Relapsed or Refractory Multiple Myeloma

作者：Baohui Wang, Xiao Huang, Jianming Sun, Yurong Qin, Hongyan Shang, Tingting Li, Guojin Wu, Min Chen, Hailin Wang, Peng Zhang, Duqing Jiang, Tongjun Liu, Mi Ye, Shengli Cai, Shoupeng Lai, Xiaoqiang Kang, Hong Ling · 发表于：Blood · 年份：2023 · DOI：10.1182/blood-2023-181395 · 被引用次数：7 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Multiple Myeloma Research and Treatments、Synthesis and Biological Evaluation

G protein-coupled receptor, class C group 5 member D (GPRC5D) is a type-C 7-pass transmembrane receptor protein that selectively overexpresses on malignant plasma cells in multiple myeloma (MM). The expression of GPRC5D is rarely seen in normal tissues or cells, and is not detectable on other hematopoietic derived cells, therefore indicating that GPRC5D may be a novel target for anti-multiple myeloma therapy. LBL-034, a novel T-cell engaging bispecific antibody targeting GPRC5D, is developed with a specifically designed molecular format and unique 2:1 structure. It showed a potent binding on cell lines with various levels of GPRC5D expression, while its binding to CD3 on Jurkat cells was much lower examined by flow cytometry. Furthermore, LBL-034 re-directed engagement of GPRC5D+ cells and T cells was validated by gating engaged cell population with flow cytometry and confirmed visually with laser scanning confocal microscopy. LBL-034 induced potent T cell dependent cell killing (TDCC) of various types of GPRC5D expressing cells (high to low expression: MM.1R, NCI-H929, MOLP-8 and RPMI 8226 cells), and elevated activation marker (CD25, CD69) expression and cytokine release (IFN-γ, TNF-α, IL-6). LBL-034 demonstrated weak binding to CD3 and minimal effects on cytokine release in the absence of GPRC5D expressing cells and it indicates that LBL-034 activates T cells only in the presence of GPRC5D target cells. LBL-034 was further examined in the MC38-GPRC5D syngeneic model and NC...