Siglec-7 glyco-immune binding mAbs or NK cell engager biologics induce potent antitumor immunity against ovarian cancers

Abstract

Ovarian cancer (OC) is a lethal gynecologic malignancy, with modest responses to CPI. Engagement of additional immune arms, such as NK cells, may be of value. We focused on Siglec-7 as a surface antigen for engaging this population. Human antibodies against Siglec-7 were developed and characterized. Coculture of OC cells with PBMCs/NKs and Siglec-7 binding antibodies showed NK-mediated killing of OC lines. Anti–Siglec-7 mAb (DB7.2) enhanced survival in OC-challenged mice. In addition, the combination of DB7.2 and anti–PD-1 demonstrated further improved OC killing in vitro. To use Siglec-7 engagement as an OC-specific strategy, we engineered an NK cell engager (NKCE) to simultaneously engage NK cells through Siglec-7, and OC targets through FSHR. The NKCE demonstrated robust in vitro killing of FSHR + OC, controlled tumors, and improved survival in OC-challenged mice. These studies support additional investigation of the Siglec-7 targeting approaches as important tools for OC and other recalcitrant cancers.

Myeloid cell networks determine reinstatement of original immune environments in recurrent ovarian cancer

“…Excluded tumours exhibited homotypic myeloid and T:myeloid networks dominated by collagen molecules interacting with ITGA1 , Claudins ( CLDN1 ) and TGFB, which are known to enhance migration and invasion in OC cells 41 and the inhibitory TREM2 / APOE axis. Finally, desert samples displayed inhibitory networks mediated by SPON2 , MRC1 , PSEN1 , NOTCH , ITGAM and SIGLEC 42,43 interactions ( Figure 3J and Table S3 ).…”