Novel Dominant Negative TNF Inhibitors for Treatment of Depression

DESCRIPTION provided by applicant Major Depressive Disorder MDD is one of the most disabling of all medical conditions worldwide with direct and indirect costs in the U S estimated to exceed $ billion per year The significance of this problem is reflected by the roughly million depressed people that do not respond to classical anti depressant treatment termed treatment resistant depression TRD and suggests an alternative mechanism Tumor Necrosis Factor TNF is reliably elevated in depressed patients and antagonism of TNF improves mood in patients with a variety of inflammatory diseases A recent trial by our group demonstrated that a subset of TRD patients improved after treatment with the non selective TNF antagonist infliximab Moreover plasma levels of the inflammatory C reactive protein CRP andgt mg L predicted efficacy suggesting that CRP may be used as a biomarker While these data are encouraging use of infliximab and other commercially available non selective TNF antagonists have significant liabilities including an increased risk of immunosuppression and demyelinating neurologic disease This occurs because these compounds inhibit both solTNF and transmembrane tmTNF solTNF drives chronic inflammatory disease while tmTNF facilitates host defense synaptic plasticity and myelination XPro is a novel selective inhibitor of solTNF that readily crosses the BBB in therapeutic concentrations Because XPro does not interact with tmTNF it does not have the undesirable off target effects associated with the currently available TNF inhibitors XPro andapos s ability to engage the target and superior safety profile make it an attractive candidate to treat TRD in patients with identifiable increased peripheral inflammation Thus this Phase I SBIR proposal seeks to establish preclinical proof of concept for the novel solTNF antagonist XPro as therapy for patients with TRD and increased inflammation The efficacy of XPro will be examined and directly compared to the commercially available anti TNF drug etanercept in terms of efficacy and target engagement in a rodent model of stress induced depression with increased inflammation As part of this application we will also validate and expand upon the biomarker strategy In addition to CRP we will also examine plasma interleukin and neutrophil gelatinase associated lipocalin NGAL an inflammatory factor specific to solTNF that has been correlated with depression in elderly patients Refinement of the biomarker strategy will increase the accuracy of identifying which TRD patients will have a therapeutic effect from anti TNF therapy This biomarker strategy is novel for psychiatry and represents an important step toward individualized medicine Once complete the results will provide justification to proceed to a Phase II proof of concept clinical trial in TRD patients with elevated peripheral blood biomarkers In support of this XPro currently has an open FDA IND for RA that is directly transferable in support of potential clinical trials in depression PUBLIC HEALTH RELEVANCE This Phase I SBIR proposal seeks to establish preclinical proof of concept for the novel solTNF antagonist XPro as therapy for patients with TRD and increased inflammation XPro has a therapeutic and safety advantage over other available anti inflammatory strategies for the treatment of the million US adults that suffer from TRD and have evidence of increased inflammation Development of a safe and specific anti soluble TNF drug that accesses the brain would represent a major advance in the therapeutic options available to depressed patients while fostering the development of a new biomarker directed immune based therapies for neuropsychiatric diseases If successful this study would yield a proof of concept to support a subsequent clinical study to be launched in the Phase II stage of our research plan