NPTXR as a novel therapeutic target: efficacy of antibody-drug conjugates in preclinical tumor models

Background The neuronal pentraxin receptor (NPTXR) is mainly expressed in the cytoplasm of a subset of neuronal cells in the cerebral cortex. While NPTXR may be involved in mediating uptake of synaptic material during synapse remodeling or synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses during embryonic development, NPTXR expression has recently been shown to be elevated in tissues from patients with gastric cancer. Methods NPTXR protein expression was evaluated in human cancer and healthy tissue samples. We then generated antibody–drug conjugates based on YB-800 (YB-800 ADCs ), a fully humanized monoclonal antibody selectively targeting NPTXR. The cross-reactivity of YB-800 and YB-800 ADCs were assessed, as well as their tumor inhibitory effects in experimental tumor models. Results NPTXR protein was highly and consistently expressed in human tissue samples from multiple cancer types but only minimally expressed, if at all, in healthy tissues. Treatment with YB-800 ADCs inhibited tumor cell proliferation/survival in engineered HEK293 cells overexpressing the human NPTXR. YB-800 ADCs were also found to have pronounced anti-tumor effects in mice bearing NPTXR-expressing HEK293 tumors at well-tolerated doses. Initial anti-tumor findings were further confirmed using a naturally occurring NPTXR-expressing human bladder PDX model. Conclusions NPTXR is an oncofetal protein that is highly expressed in multiple human cancers but minimally expressed in healthy tissues. We have established NPTXR as a new tumor marker and have developed antibody–drug conjugates using YB-800, a novel, first-in-class, humanized monoclonal antibody targeting the human NPTXR. Initial results demonstrate that YB-800 ADCs have pronounced anti-tumor effects in vivo in NPTXR-expressing cancer cells. Continued evaluation of YB-800 ADCs is warranted.