Potent Cytolytic Activity and Specific IL15 Delivery in a 2nd Generation Trispecific Killer Engager

Research output: Contribution to journalArticlepeer-review

Abstract

Natural killer (NK) cells are potent immune modulators that can quickly lyse tumor cells and elicit inflammatory responses. These characteristics make them ideal candidates for immunotherapy. However, unlike T cells, NK cells do not possess clonotypic receptors capable of specific antigen recognition and cannot expand via activating receptor signals alone. To enable NK cells with these capabilities, we created and have previously described a Tri-specific Killer Engager (TriKETM) platform capable of inducing antigen specificity and cytokine-mediated NK cell expansion. TriKE molecules have three arms: (i) a single chain variable fragment (scFv) against the activating receptor CD16 on NK cells, to trigger NK cell activation; (ii) an scFv against a tumor-associated antigen (CD33 here), to induce specific tumor target recognition; and (iii) an IL15 moiety, to trigger NK cell expansion and priming. Here, we demonstrated that by modifying the anti-CD16 scFv with a humanized single domain antibody against CD16, we improved TriKE functionality. A CD33-targeting second-generation TriKE induced stronger and more specific NK cell proliferation without T-cell stimulation, enhanced in vitro NK cell activation and killing of CD33-expressing targets, and improved tumor control in preclinical mouse models. Given these improved functional characteristics, we propose rapid translation of second-generation TriKEs into the clinic.

Original languageEnglish (US)
JournalCancer Immunology Research
DOIs
StateE-pub ahead of print - Jul 13 2020

Bibliographical note

Copyright ©2020, American Association for Cancer Research.

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'Potent Cytolytic Activity and Specific IL15 Delivery in a 2nd Generation Trispecific Killer Engager'. Together they form a unique fingerprint.

Cite this