YB-811, a novel antibody drug conjugate targeting the tumor-selective human neuronal pentraxin receptor shows pronounced efficacy in experimental tumor models

The human neuronal pentraxin receptor (NPTXR) gene encodes a type II transmembrane protein that functions as a trans-synaptic organizer and anchors neuronal pentraxin complexes to plasma membranes in a subset of neuronal cells of the hippocampus and cerebral cortex. Beside its synaptic functions in the brain, NPTXR is not present in other organs and therefore does not have any physiological role; hence NPTXR −/− mice showed no abnormalities in reproduction, development, metabolism, or motor function. Recent immunohistochemistry studies performed with a fully humanized monoclonal antibody (YB-800) targeting NPTXR with high affinity have revealed expression of membrane-associated NPTXR protein in a wide variety of solid tumors (but not in adjacent healthy tissues and healthy tissue samples) with a high prevalence (up to 98%) and H-scores (up to 300); e.g., in bladder, cervix, non-TNBC, NSCLC, and pancreas tumor samples. These results strongly support the rationale for the design of a YB-800-based antibody drug conjugate (ADC) as novel option for safe therapeutic intervention in Oncology. A novel ADC (YB-811) was engineered with YB-800 linked to 4 monomethylauristatin F molecules ( via non-cleavable linkers), and 4 exatecan molecules ( via cleavable linkers). YB-811 was evaluated in multiple experimental tumor models in both cell-based assays and in vivo tumor studies. Results clearly indicate concentration- and time-dependent effect on tumor cell proliferation and survival, as well as pronounced anti-tumor activity - tumor growth inhibition/regression - in established tumor-bearing athymic mice. Taken together, these results strongly support further exploration of the potential therapeutic benefit of YB-811.