Summary of the technology
Dr. Zvika Granot, from the School of Medicine-IMRIC-Developmental Biology and Cancer Research, is working on a innovative approach for Neutrophil specific targeting of TGF-beta signaling as a novel anti-cancer therapy (see attached summary and several papers)
Project ID : 6-2015-4241
Description of the technology
Neutrophils are potent effector cells in a wide number of infectious, inflammatory and cancerous conditions. Modulation of Neutrophil functions in these conditions may have significant therapeutic benefits and effects on disease progression. However, Neutrophils are short lived and cannot be manipulated ex-vivo. Neutrophil specific targeting allows modulation of neutrophil function in patients with minimal off-target effects.
- Using Neutrophil-Specific Nanoparticles to modify Neutrophil function as a mode of Immunotherapy.
- We identified Neutrophil specific binding peptides.
- PLGA nanoparticles decorated with these peptides are taken up specifically by neutrophils.
- Drug containing nanoparticles modify neutrophil function.
- Targeted neutrophils accumulate in site of disease.
- Neutrophil specific targeting of TGFbeta blocks metastatic progression.
The neutrophil specific platform may be used to modulate neutrophil function using drugs that may have adverse consequences when administered systemically. Using this platform of very low drug concentrations will have the desired effect while having minimal to no off target effects.
Neutrophils accumulate and play a critical role in a wide range of clinical settings. Accordingly, while our proof of concept shows efficacy in a preclinical model of metastasis,modulating neutrophil function specifically using this platform may be used to treat many other conditions where neutrophils play a role such as COPD, Neutrophilic Asthma, Sepsis, Neutrophil dematoses, Stroke, etc.
We have identified peptides binding specifically to neutrophils in both mouse and human. We use these peptides to decorate PLGA nanoparticles which may contain any desirable payload. These nanoparticles are taken up specifically by neutrophils in vivo (A and B) and accumulate at sites of inflammation. Accordingly, neutrophil specific nanoparticles may be used to modulate neutrophil function in vivo. As a proof of concept we tested the consequences of blocking TGFbeta in neutrophils in a preclinical model of metastatic breast cancer. Neutrophil specific nanoparticles containing SB431542 (a TGFbeta blocker) efficiently block the phosphorylation of Smad2 (C) – an indication for activation of canonical TGFbeta signaling. When introduced into the circulation of mice with mammary tumor lung metastases, nanoparticles containing TGFbeta blocker dramatically reduced metastatic outgrowth (E and F).