NK-Cell-Mediated Targeting of Various Solid Tumors Using a B7-H3 Tri-Specific Killer Engager In Vitro and In Vivo.
Daniel A ValleraSoldano FerroneBehiye KodalPeter HinderlieLaura BendzickBrianna EttestadCaroline HallstromNicholas A ZorkoArpit RaoNaomi FujiokaCharles J RyanMelissa A GellerJeffrey S MillerMartin FelicesPublished in: Cancers (2020)
We improved the bispecific antibody platform that primarily engages natural killer (NK) cells to kill cancer cells through antibody-dependent cellular cytotoxicity (ADCC) by adding IL-15 as a crosslinker that expands and self-sustains the effector NK cell population. The overall goal was to target B7-H3, an established marker predominantly expressed on cancer cells and minimally expressed on normal cells, and prove that it could target cancer cells in vitro and inhibit tumor growth in vivo. The tri-specific killer engager (TriKETM) was assembled by DNA shuffling and ligation using DNA encoding a camelid anti-CD16 antibody fragment, a wild-type IL-15 moiety, and an anti-B7-H3 scFv (clone 376.96). The expressed and purified cam1615B7H3 protein was tested for in vitro NK cell activity against a variety of tumors and in vivo against a tagged human MA-148 ovarian cancer cell line grafted in NSG mice. cam1615B7H3 showed specific NK cell expansion, high killing activity across a range of B7-H3+ carcinomas, and the ability to mediate growth inhibition of aggressive ovarian cancer in vivo. cam1615B7H3 TriKE improves NK cell function, expansion, targeted cytotoxicity against various types of B7-H3-positive human cancer cell lines, and delivers an anti-cancer effect in vivo in a solid tumor setting.
Keyphrases
- nk cells
- wild type
- endothelial cells
- circulating tumor
- induced apoptosis
- induced pluripotent stem cells
- cancer therapy
- cell free
- single molecule
- pluripotent stem cells
- regulatory t cells
- dendritic cells
- high throughput
- drug delivery
- immune response
- squamous cell carcinoma
- binding protein
- young adults
- skeletal muscle
- cell death
- endoplasmic reticulum stress
- circulating tumor cells
- african american
- type iii
- protein protein
- lymph node metastasis