Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET® CC-96191
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Therapeutics
2.2. Lentiviral Expression Vectors
2.3. Surface Plasmon Resonance (SPR)
2.4. Peripheral Blood Mononuclear Cells and Primary Human NK Cells
2.5. Secreted Cytokine Measurements
2.6. Human NK and Acute Leukemia Cell Lines
2.7. Quantification of CD33 Expression
2.8. Assessment of Binding of CC-96191 to CD33FL and CD33∆E2
2.9. Quantification of Drug-Induced Cytotoxicity
2.10. Frequency of CD33 SNPs
2.11. Primary AML Aspirates
2.12. Statistical Considerations
3. Results
3.1. CC-96191 Simultaneously Binds CD33, NKG2D, and CD16a with Greater Strength Than Single Binding to NKG2D or CD16a
3.2. Co-engagement of CD16a, NKG2D, and CD33 Is Required for Optimal Cytolytic Activity of CC-96191 against CD33+ AML Cells
3.3. Effect of CD33 Expression and CD33 SNPs on CC-96191-Induced Cytotoxicity
3.4. Impact of Soluble MICA and CD33 on CC-96191-Induced Cytotoxicity
3.5. CC-96191-Induced Cytokine Secretion, Cellular Activation, and Cytolysis by Human NK Cells and PBMCs
3.6. CC-96191-Induced Selective Destruction of Leukemia Cells in Bone Marrow Samples from Patients with AML
3.7. Effect of ABC Transporter Protein Expression on CC-96191-Induced Cytotoxicity
3.8. Effect of Anti-Apoptotic BCL-2 Family Proteins on CC-96191-Induced Cytotoxicity
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cell Line | CD33 Expression | KHYG-1CD16a Cytotoxicity | CC-96191 Specific Cytotoxicity | ||||
---|---|---|---|---|---|---|---|
10 pM | 50 pM | 500 pM | 1 nM | 5 nM | |||
EOL-1 | ++ | 26.0 ± 15.4 | ND | ND | 52.7 ± 3.2 | 62.3 ± 3.8 | 69.0 ± 4.6 |
HL-60 | ++ | 8.2 ± 3.5 | ND | 2.0 ± 4.2 | 14.0 ± 3.6 | 30.7 ± 5.4 | 46.7 ± 3.5 |
K562 | + | 91.4 ± 4.9 | ND | ND | ND | ND | ND |
KG-1 | + | 12.4 ± 1.8 | ND | ND | No effect | 7.3 ± 8.3 | 5.0 ± 6.5 |
ML-1 | ++ | 32.6 ± 8.5 | No effect | No effect | 34.3 ± 22.2 | 62.0 ± 15.6 | ND |
ML1CD33KO | − | 22.8 ± 12.7 | No effect | No effect | No effect | No effect | No effect |
MOLM-13 | ++ | 25.2 ± 13.8 | 2.7 ± 1.8 | 13.3 ± 4.5 | 94.7 ± 2.4 | 94.0 ± 3.1 | ND |
MV4;11 | ++ | 34.9 ± 9.4 | ND | ND | 45.7 ± 17.3 | 51.0 ± 19.1 | 53.3 ± 18.7 |
OCI-AML3 | + | 22.5 ± 12.9 | No effect | 5.7 ± 1.3 | 6.0 ± 3.1 | 1.3 ± 3.4 | ND |
REH | − | 25.7 ± 13.2 | No effect | No effect | No effect | ND | ND |
REHCD33FL | ++++ | 16.7 ± 7.9 | 21.0 ± 4.4 | 73.0 ± 7.8 | 89.0 ± 4.0 | ND | ND |
TF-1 | +++ | 28.6 ± 1.6 | ND | ND | 68.0 ± 4.6 | 74.7 ± 4.3 | 78.3 ± 6.1 |
TF-1CD33KO | − | 31.6 ± 6.5 | ND | ND | 0.3 ± 3.3 | No effect | No effect |
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Lunn-Halbert, M.C.; Laszlo, G.S.; Erraiss, S.; Orr, M.T.; Jessup, H.K.; Thomas, H.J.; Chan, H.; Jahromi, M.A.; Lloyd, J.; Cheung, A.F.; et al. Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET® CC-96191. Cancers 2024, 16, 877. https://doi.org/10.3390/cancers16050877
Lunn-Halbert MC, Laszlo GS, Erraiss S, Orr MT, Jessup HK, Thomas HJ, Chan H, Jahromi MA, Lloyd J, Cheung AF, et al. Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET® CC-96191. Cancers. 2024; 16(5):877. https://doi.org/10.3390/cancers16050877
Chicago/Turabian StyleLunn-Halbert, Margaret C., George S. Laszlo, Sarah Erraiss, Mark T. Orr, Heidi K. Jessup, Heather J. Thomas, Henry Chan, Mahan A. Jahromi, Jonathan Lloyd, Ann F. Cheung, and et al. 2024. "Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET® CC-96191" Cancers 16, no. 5: 877. https://doi.org/10.3390/cancers16050877