A HER2 tri-specific NK cell engager mediates efficient targeting of human ovarian cancer

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Abstract

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 (TriKE TM) 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.

Original languageEnglish (US)
Article number3994
JournalCancers
Volume13
Issue number16
DOIs
StatePublished - Aug 2 2021

Bibliographical note

Funding Information:
Funding: This work was supported by the Minnesota Ovarian Cancer Alliance (MOCA), the Randy Shaver Cancer Research and Community Fund, the Sarcoma Foundation of America, Minnesota Masonic Charities, and the Killebrew–Thompson Memorial Fund. It was also sup-ported by the US Public Health Service Grant R01-CA72669, P01-CA65493, P01-CA111412, R35 CA197292, and P30 CA077598 awarded by the NCI and the NIAID, DHHS.

Funding Information:
This work was supported by the Minnesota Ovarian Cancer Alliance (MOCA), the Randy Shaver Cancer Research and Community Fund, the Sarcoma Foundation of America, Minnesota Masonic Charities, and the Killebrew?Thompson Memorial Fund. It was also supported by the US Public Health Service Grant R01-CA72669, P01-CA65493, P01-CA111412, R35 CA197292, and P30 CA077598 awarded by the NCI and the NIAID, DHHS.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • ADCC
  • Bispecific antibodies
  • Carcinoma
  • HER2
  • IL-15
  • Innate immunotherapy
  • NK cells
  • Ovarian cancer
  • TriKEs

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