Wistar Scientists Engineer New NK cell Engaging Immunotherapy Approaches to Target and potentially Treat reca

 

To combat ovarian cancer treatment resistance, the team hypothesized that they might be able to engage not only the traditional T cell immune arm of the immune system which PD-1 and known checkpoint inhibitors (CPI) activate, but also implement a strategy to activate Natural killer cells (NK cells), a subset of important anti-tumor immune cells, through a conserved glyco-immune marker found on the surface of most NK cells called Siglec-7 (Sialic acid-binding immunoglobulin-type lectin). NK cells have been recently described to express Siglec-7, so the team tested two new strategies to engage and activate NK cells against ovarian cancer through Siglec-7. 

 

The first approach used human monoclonal antibodies (mAb) discovered and developed at Wistar and novel assays to visualize and demonstrate that certain anti-Siglec-7 mAbs could activate human NK cells — which, in the presence of the antibodies, responded against multiple human OC cell lines. These now-activated NK cells would kill OC but not non-cancer cells with the Siglec-7 mAb treatment. 

 

The researchers demonstrated that multiple OC carrying mutations, including BRCA1 and BRCA2, could be targeted by Siglec-7 antibodies through activated NK cells. The group moved to study the treatment of OC in a humanized mouse model and observed that the Siglec-7 treatment could impact OC growth slowing the tumors and increasing the animals’ survival.  

 

Having demonstrated the feasibility of utilizing a Siglec-7 mAb in OC models, the team thought there were additional ways to use the Siglec-7 mAb to further focus on OC disease. They hypothesized that directly fusing the Siglec-7 reactive binding site of the Siglec-7 mAb to a second mAb that uniquely binds late OC through a molecule named Follicle Stimulating Hormone receptor (FSHR), which they had previously developed, would create a targeted Siglec-7 bispecific antibody that could bind through two distinct targets creating a new class of NK cell engagers (NKCE). 

 

The team sought to test whether this Siglec-7 NKCE approach would be effective through the direct linkage of potentially killer NK cells to a guided missile aimed specifically at OC, which would open up a new path to develop additional Siglec-7 based immunotherapeutic approaches. In both bench and humanized mouse challenge studies, the Siglec-7-NKCE was effective at targeting OC, activating NK cells in local proximity and efficiently killing multiple OC. 

 

BACA JUGA:Daya Tarik Utama Bugatti Adalah Eksklusivitasnya Kombinasi Mewah dan Kecepatan

BACA JUGA: Jelang Penetapan DCT, 11 Partai Ganti 15 Bacaleg! Apa Anda Termasuk?

 

Both Siglec-7 technologies (mAbs and NKCEs) demonstrated an ability to recruit and activate the NK cell population, shrink tumors and prolong survival in the models studied. The observation of on-target specificity of the approaches suggests that cancer’s apparent Siglec vulnerability can be exploited therapeutically, perhaps with limited toxicity — a promising sign for the future of anti-cancer Siglec research, but the team cautions that more work in this regard is important. 

Sumber: