A HER2 Tri-Specific NK Cell Engager Mediates Efficient Targeting of Human Ovarian Cancer.

Abstract

Simple SummaryHER2 is a marker known to be over-expressed on breast cancer, rendering it one of the most useful solid tumor targets for antibody-based therapies. Despite expression on ovarian cancer, results targeting HER2 in this setting have been disappointing, thus requiring more aggressive approaches. Natural killer (NK) cells are known as principal mediators of cancer cell killing, but cancer cells find ways to deter them. We devised a tri-specific biological drug containing antibody fragments that simultaneously binds NK cells and cancer cells and at the same time delivers a natural cytokine signal that triggers robust NK cell expansion. In vitro studies show the drug augments NK cell killing of a number of HER2-positive human cell lines, while enhancing NK cell activation and proliferation. Studies in mice engrafted with human ovarian cancer showed the drug has anti-tumor efficacy, clearly demonstrating its ability to bolster NK cells in their ability to contain tumor cell growth. Clinical studies validated antibodies directed against HER2, trastuzumab, and pertuzumab, as useful methodology to target breast cancer cases where HER2 is expressed. The hope was that HER2 targeting using these antibodies in ovarian cancer patients would prove useful as well, but clinical studies have shown lackluster results in this setting, indicating a need for a more comprehensive approach. Immunotherapy approaches stimulating the innate immune system show great promise, although enhancing natural killer (NK) function is not an established mainstream immunotherapy. This study focused on a new nanobody platform technology in which the bispecific antibody was altered to incorporate a cytokine. Herein we describe bioengineered CAM1615HER2 consisting of a camelid VHH antibody fragment recognizing CD16 and a single chain variable fragment (scFv) recognizing HER2 cross-linked by the human interleukin-15 (IL-15) cytokine. This tri-specific killer engager (TriKETM) showed in vitro prowess in its ability to kill ovarian cancer human cell lines. In addition, we demonstrated its efficacy in inducing potent anti-cancer effects in an in vivo xenograft model of human ovarian cancer engrafting both cancer cells and human NK cells. While previous approaches with trastuzumab and pertuzumab faltered in ovarian cancer, the hope is incorporating targeting and cytokine priming within the same molecule will enhance efficacy in this setting.