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-800ADCs), a fully humanized monoclonal antibody selectively targeting NPTXR. The cross-reactivity of YB-800 and YB-800ADCs 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-800ADCs inhibited tumor cell proliferation/survival in engineered HEK293 cells overexpressing the human NPTXR. YB-800ADCs 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-800ADCs have pronounced anti-tumor effects in vivo in NPTXR-expressing cancer cells. Continued evaluation of YB-800ADCs is warranted.