학술논문
Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET® CC-96191
Document Type
article
Author
Margaret C. Lunn-Halbert; George S. Laszlo; Sarah Erraiss; Mark T. Orr; Heidi K. Jessup; Heather J. Thomas; Henry Chan; Mahan A. Jahromi; Jonathan Lloyd; Ann F. Cheung; Gregory P. Chang; Tanmay Dichwalkar; Daniel Fallon; Asya Grinberg; Eduardo Rodríguez-Arbolí; Sheryl Y. T. Lim; Allie R. Kehret; Jenny Huo; Frances M. Cole; Samuel C. Scharffenberger; Roland B. Walter
Source
Cancers, Vol 16, Iss 5, p 877 (2024)
Subject
Language
English
ISSN
2072-6694
Abstract
Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET®. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells. CC-96191 was broadly active against human leukemia cells in a strictly CD33-dependent manner, with maximal efficacy requiring the co-engagement of CD16a and NKG2D. A frequent CD33 single nucleotide polymorphism, R69G, reduced CC-96191 potency but not maximal activity, likely because of reduced CD33 binding. Similarly, the potency, but not the maximal activity, of CC-96191 was reduced by high concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact activity. In the presence of CD33+ AML cells, CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a CD33/CD3 bispecific antibody. While CC-96191-mediated cytolysis was not affected by ABC transporter proteins, it was reduced by anti-apoptotic BCL-2 family proteins. Finally, in patient marrow specimens, CC-96191 eliminated AML cells but not normal monocytes, suggesting selectivity of TriNKET-induced cytotoxicity toward neoplastic cells. Together, these findings support the clinical exploration of CC-96191 as in NCT04789655.