A novel monoclonal antibody-based anti-NK cell anti-inflammatory strategy for treating autoimmune and checkpoint inhibitor induced myocarditis

Summary The Problem: Despite current therapies, the prognosis of various forms of acute and chronic inflammation of the heart (myocarditis) remains poor. Immune reactions that attack a patient’s own tissues (autoimmune disease) is one major cause of myocarditis. Additionally, one of the complications of immune checkpoint inhibitors (ICI), which attack cancer cells though activation of inflammation, is myocarditis. Innovation: Inflammation involves multiple molecules and multiple redundant pathways. The anti-inflammatory monoclonal antibodies (mAbs) forming the basis of treatment of inflammation-related diseases target a single molecule and a single inflammatory pathway. Therapeutic efficacy is thereby limited. NK cells are major orchestrators of multiple inflammatory pathways. Inflamma Therapeutics (IFT) therefore developed a novel mAb—IFT100—that depletes NK cells. By inhibiting NK cells IFT100 inhibits multiple inflammatory pathways. As proof-of-concept of the efficacy of an NK cell depleting strategy, we demonstrated that an anti-NK cell mAb that depletes mouse NK cells improves myocardial function in mice with acute heart attacks or with chronic heart failure. IFT therefore decided to develop an anti-human NK cell mAb—IFT100—to serve as an immunosuppressive therapeutic agent to treat inflammation-exacerbated human disease. IFT found that IFT 101 binds to and depletes human NK cells. IFT100 was sequenced and patents submitted. The AIMS of the current proposal, using IFT100: Aim 1: Determine the dose response for in-vivo NK cell depletion in mice. Aim 2: Determine the impact of NK cell depletion on the prevention of Experimental Autoimmune Myocarditis. Aim 3: Determine the impact of NK cell depletion on the prevention of Experimental Autoimmune Myocarditis with or without the burden of ICI treatment. Aim 4: Humanize our mAb. In this project we will be validating the ability of our specific mAb (IFT100) to improve autoimmune-induced and ICI-induced myocarditis. Importantly, however, we believe IFT100 will also be effective for improving outcomes in many other diseases that are worsened by excessive inflammation. These include myocardial dysfunction in patients with chronic heart failure, with cardiogenic shock, and with acute MI. Another important additional therapeutic target for IFT100 is the massive inflammatory response responsible for most of the deaths seen in Covid-19. Each of these conditions has no current effective therapy and, as such, constitute conditions for which there are major unmet therapeutic needs.Narrative Severe forms of inflammation-induced acute and chronic myocarditis caused by autoimmune disease or occurring as a complication of checkpoint inhibitor therapy for cancer patients have a poor prognosis, even with available therapies. Stimulated by the knowledge that inflammation involves multiple pathways, and that inhibition of a single pathway (as current monoclonal antibodies do) is intrinsically limited in efficacy, Inflamma Therapeutics developed a novel mAb that inhibits NK cells, one of the major orchestrators of multiple inflammatory pathways. By inhibiting NK cells, we inhibit multiple inflammatory pathways, a more potent therapeutic strategy for improving outcomes not only for myocarditis, but in many other diseases that are worsened by excessive inflammation.