2. Academic Validation
  3. A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy

  • Cancer Immunol Res. 2021 Sep;9(9):1071-1087. doi: 10.1158/2326-6066.CIR-20-1002.
Michelle K Becker-Hapak 1,  Niraj Shrestha 2,  Ethan McClain 1,  Michael J Dee 2,  Pallavi Chaturvedi 2,  Gilles M Leclerc 2,  Lynne I Marsala 1,  Mark Foster 1,  Timothy Schappe 1,  Jennifer Tran 1,  Sweta Desai 1,  Carly C Neal 1,  Patrick Pence 1,  Pamela Wong 1,  Julia A Wagner 1,  David A Russler-Germain 1,  Xiaoyun Zhu 2,  Catherine M Spanoudis 2,  Victor L Gallo 2,  Christian A Echeverri 2,  Laritza L Ramirez 2,  Lijing You 2,  Jack O Egan 2,  Peter R Rhode 2,  Jin-An Jiao 2,  Gabriela J Muniz 2,  Emily K Jeng 2,  Caitlin A Prendes 2,  Ryan P Sullivan 3,  Melissa M Berrien-Elliott 1,  Hing C Wong 2,  Todd A Fehniger 4
Affiliations

Affiliations

  • 1 Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri.
  • 2 HCW Biologics Inc., Miramar, Florida.
  • 3 Wugen, Inc., Saint Louis, Missouri.
  • 4 Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri. tfehnige@wustl.edu.
PMID: 34244297 DOI: 10.1158/2326-6066.CIR-20-1002
Abstract

Natural killer (NK) cells are a promising cellular therapy for Cancer, with challenges in the field including persistence, functional activity, and tumor recognition. Briefly, priming blood NK cells with recombinant human (rh)IL-12, rhIL-15, and rhIL-18 (12/15/18) results in memory-like NK cell differentiation and enhanced responses against Cancer. However, the lack of available, scalable Good Manufacturing Process (GMP)-grade reagents required to advance this approach beyond early-phase clinical trials is limiting. To address this challenge, we developed a novel platform centered upon an inert tissue factor scaffold for production of heteromeric fusion protein complexes (HFPC). The first use of this platform combined IL-12, IL-15, and IL-18 Receptor engagement (HCW9201), and the second adds CD16 engagement (HCW9207). This unique HFPC expression platform was scalable with equivalent protein quality characteristics in small- and GMP-scale production. HCW9201 and HCW9207 stimulated activation and proliferation signals in NK cells, but HCW9207 had decreased IL-18 Receptor signaling. RNA Sequencing and multidimensional mass cytometry revealed parallels between HCW9201 and 12/15/18. HCW9201 stimulation improved NK cell metabolic fitness and resulted in the DNA methylation remodeling characteristic of memory-like differentiation. HCW9201 and 12/15/18 primed similar increases in short-term and memory-like NK cell cytotoxicity and IFNγ production against leukemia targets, as well as equivalent control of leukemia in NSG mice. Thus, HFPCs represent a protein engineering approach that solves many problems associated with multisignal receptor engagement on immune cells, and HCW9201-primed NK cells can be advanced as an ideal approach for clinical GMP-grade memory-like NK cell production for Cancer therapy.

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