Targeting integrin outside-in signaling for treating sepsis

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In severe sepsis, systemic inflammation induced by infection leads to vascular leakage, microvascular thrombosis, disseminated intravascular coagulation (DIC), multiple organ dysfunction, hemorrhage and circulatory collapse, resulting in high mortality. Antibiotics and standard care regimens are helpful, but ultimately ineffective for many patients. Despite years of intensive research, the only new drug FDA approved for treatment of sepsis is activated protein C (APC, Xigris®), which prevents thrombosis and reduces inflammation by inhibiting thrombin generation. However, Xigris also causes hemorrhage, which outweighed its benefits and resulted in withdrawal from the market. Thus, there is an urgent unmet need for new life-saving treatment of sepsis. Here, we propose to develop a new drug for sepsis treatment, which potently inhibits both thrombosis and inflammation without causing bleeding. This innovative drug targets a novel integrin signaling mechanism recently discovered in the lab of Xiaoping Du, co-investigator of this application (Gong et al Science 2010, Shen et al, Nature 2013, Shen MBoC 2015, Pang Blood 2018), who showed that integrin outside-in signaling requires direct interaction between the G protein subunit Galpha13 and an ExE motif conserved in the cytoplasmic domain of several integrin Beta subunits (including Beta3 in platelets and Beta2 in leukocytes). Disruption of Galpha13-integrin interaction abolishes outside-in signaling without affecting the ligand binding function of integrins important for hemostasis. We designed a selective peptide inhibitor of the Beta3 Galpha13 binding ExE motif that potently inhibited occlusive intravascular thrombosis without causing excessive bleeding (Shen et al, Nature, 2013). Because integrin outside-in signaling is critical not only in thrombosis but also in inflammation, we designed an ExE motif peptide, MB2mP6, that inhibits Galpha13 interaction with Beta3 integrins in platelets and also Beta2 integrins in leukocytes. In Phase I studies, we showed that treatment of mice with MB2mP6 immediately after or 6 h after sepsis onset potently inhibits inflammation and thrombosis in septic mice, significantly reducing mortality. This drug also protects lungs from vascular leakage and microthrombosis that can lead to ARDS, a severe consequence of sepsis and a major cause of mortality of SARS-coronavirus 2 infection (COVID19) as well as influenza. Importantly, this new drug did not exacerbate hemorrhage induced by either physical injury or inflammation. We further developed novel lipid-stabilized high-loading peptide nanoparticles (HLPN) for efficient in vivo drug delivery. In this Phase II application, we propose to (1) Evaluate the efficacy of MB2mP6 as an adjunct to antibiotics and standard care in treating sepsis and ARDS following bacterial and viral infection. (2) Evaluate the safety (absence of anti-hemostatic activity) and toxicity of MB2mP6 (3) Scale up production of a GMP-grade new drug and IND preparation and submission. This novel drug that targets thrombosis and excess inflammation, without impairing hemostasis and vascular integrity, holds promise for treating sepsis as well as ARDS arising from sepsis as well as viral infections.