NK-cell-mediated targeting of various solid tumors using a B7-H3 tri-specific killer engager in vitro and in vivo

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Abstract

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 (TriKE™) 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.

Original languageEnglish (US)
Article number2659
Pages (from-to)1-18
Number of pages18
JournalCancers
Volume12
Issue number9
DOIs
StatePublished - Sep 18 2020

Bibliographical note

Funding Information:
This work was supported in part by the US Public Health Service Grant R01-CA72669, P01-CA65493, P01-CA111412, R35 CA197292, R03-CA2-31766, R03-CA2-16114, 2T32HL007062 Hematology Research Training Program T32 at the University of Minnesota, and P30 CA077598 awarded by the NCI and the NIAID, DHHS. It was also supported by the Randy Shaver Cancer Research and Community Fund, the Mayo Partnership Award, the Lion Fund, the Minnesota Ovarian Cancer Alliance, the CETI Translational Award from the Masonic Cancer Center, Minnesota Masonic Charities, Sarcoma Foundation of America, and the Killebrew?Thompson Memorial Fund. Acknowledgments: We would like to acknowledge the Translational Therapy Laboratory, Flow Cytometry, and Imaging cores at the University of Minnesota for their excellent services. We would also like to thank Dan Kaufman for his assistance in creation of the MA-148-luc line.

Funding Information:
Funding: This work was supported in part by the US Public Health Service Grant R01-CA72669, P01-CA65493, P01-CA111412, R35 CA197292, R03-CA2-31766, R03-CA2-16114, 2T32HL007062 Hematology Research Training Program T32 at the University of Minnesota, and P30 CA077598 awarded by the NCI and the NIAID, DHHS. It was also supported by the Randy Shaver Cancer Research and Community Fund, the Mayo Partnership Award, the Lion Fund, the Minnesota Ovarian Cancer Alliance, the CETI Translational Award from the Masonic Cancer Center, Minnesota Masonic Charities, Sarcoma Foundation of America, and the Killebrew–Thompson Memorial Fund.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

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

PubMed: MeSH publication types

  • Journal Article

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