How Do mAbs Make Use of Complement to Kill Cancer Cells? The Role of Ca2+
Abstract
:1. Introduction
2. Nucleated Cells Are More Complicated: Important Questions
3. Experimental Strategies
4. Quantitation and Visualization of Early Steps in mAb-Mediated CDC: In Vitro and In Vivo Studies
5. C3b Deposition Kinetics, a Key Intermediate Step in CDC; the “Discovery” of Streamers
6. On the Importance of Ca2+
7. Hexamer-Forming mAbs are More Effective in Activating C
7.1. Cell-Bound Hexamer-Forming mAbs Bind C1q
7.2. Four-Color Confocal Microscopy Movies
7.3. Kinetics of CDC Monitored by Multicolor HRDI
8. On the Role of C9
9. Ca2+ Appears to be the Key: Implications
10. The Future
11. Summary
12. Patents
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
7AAD | 7-aminoactinomycin D |
Al | Alexa dye |
APC | alternative pathway of complement |
BDSS | bright detail similarity score |
C | complement |
CDC | complement-dependent cytotoxicity |
CLL | chronic lymphocytic leukemia |
EAC | Ehrlich ascites cell |
FcεRI | the high-affinity receptor for the Fc region of IgE |
FcγR | receptor for the Fc region of IgG |
GMF | geometric mean fluorescence |
HRDI | high-resolution digital imaging in a flow cytometry environment |
MAC | membrane attack complex |
mAb | monoclonal antibody |
NHS | normal human serum |
OFA | ofatumumab |
PI | propidium iodide |
RTX | rituximab |
TNTs | tunneling nanotubules |
TMRME | tetramethylrhodamine methyl ester |
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Step | Time Frame * | Method | Figure | References |
---|---|---|---|---|
mAb binding | 30 s | Flow cytometry | 8 | [16] |
C1q binding and colocalization with mAb | 60 s | Flow cytometry | 2, 8 | [16,17] |
C3b deposition and mAb colocalization | 90 s | Flow cytometry, high-resolution digital imaging (HRDI) | 3, 4, 10 | [16,18,19] |
C9 binding and colocalization of C9/C3b/mAb | 60–120 s | HRDI, confocal | 11, 12 | [20] |
Ca2+ influx, transition-state intermediate | 40–135 s | Confocal, flow cytometry | 9, 10, 15, 16 | [16,21] |
tunneling nanotubule (TNT) generation | 120 s | Spinning disk | 4, 7 | [19,22] |
mitochondrial poisoning | 180 s 60–180 s | HRDI, confocal | 9–11 | [16,20] |
decay of transition-state intermediate | 225 s | Confocal | 9, 10, 15, 16 | [16,21] |
MAC formation and cell death | 60–240 s | Confocal | 8–10, 15 | [16,20,21] |
Expt. 1 | Expt. 2 | Expt. 3 a | |||||||
---|---|---|---|---|---|---|---|---|---|
Al647 mAb (GMF) b | Al488 C1q (GMF) | BDSS c | Al647 mAb (GMF) | Al488 C1q (GMF) | BDSS | Al647 mAb (GMF) | Al488 C1q (GMF) | BDSS | |
Al647 OFA | 181,000 | 162,000 | 3.0 | 116,000 | 113,000 | 3.4 | 206,000 | 30,000 | 2.5 |
Al647 RTX | 186,000 | 7500 | 0.9 | 61,000 | 6600 | 2.1 | 155,000 | 2200 | 1.0 |
Al647 7D8 d | 133,000 | 2300 | 0.6 | 104,000 | 1000 | 0.9 | 210,000 | 1300 | 0.7 |
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Taylor, R.P.; Lindorfer, M.A. How Do mAbs Make Use of Complement to Kill Cancer Cells? The Role of Ca2+. Antibodies 2020, 9, 45. https://doi.org/10.3390/antib9030045
Taylor RP, Lindorfer MA. How Do mAbs Make Use of Complement to Kill Cancer Cells? The Role of Ca2+. Antibodies. 2020; 9(3):45. https://doi.org/10.3390/antib9030045
Chicago/Turabian StyleTaylor, Ronald P., and Margaret A. Lindorfer. 2020. "How Do mAbs Make Use of Complement to Kill Cancer Cells? The Role of Ca2+" Antibodies 9, no. 3: 45. https://doi.org/10.3390/antib9030045