Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease
Abstract
:1. Introduction
2. Experimental
2.1. mAb Conjugation and Radiolabeling
2.2. Cell Lines
2.3. In Vitro Studies
Radioimmunoassays
2.4. In Vivo Studies
2.4.1. Biodistributions
2.4.2. Therapy Studies
2.4.3. Statistical Analyses
2.4.4. γ-Scintigraphy
3. Results and Discussion
3.1. In Vitro Analysis of 177Lu-Trastuzumab
3.2. Direct Quantitation of 177Lu-Trastuzumab Tumor Targeting and Normal Organ Distribution
Time (h) | ||||||
---|---|---|---|---|---|---|
RIC | Tissue | 24 | 48 | 72 | 96 | 168 |
Trastuzumab | Blood | 12.68 ± 3.08 | 13.72 ± 0.79 | 9.74 ± 2.67 | 10.06 ± 2.75 | 3.85 ± 1.50 |
Tumor | 16.24 ± 4.18 | 19.08 ± 3.23 | 21.75 ± 11.66 | 24.70 ± 10.29 | 19.59 ± 9.84 | |
Liver | 7.80 ± 2.52 | 5.72 ± 1.57 | 6.39 ± 1.40 | 6.70 ± 1.71 | 5.18 ± 2.87 | |
Spleen | 5.63 ± 1.45 | 3.75 ± 2.33 | 6.38 ± 2.64 | 5.69 ± 2.12 | 4.11 ± 2.12 | |
Kidney | 5.33 ± 0.46 | 3.87 ± 2.38 | 4.47 ± 1.48 | 4.24 ± 0.62 | 2.54 ± 0.48 | |
Lung | 6.51 ± 1.66 | 6.57 ± 0.34 | 5.42 ± 1.28 | 3.98 ± 1.75 | 2.10 ± 0.81 | |
Heart | 5.06 ± 1.50 | 4.87 ± 0.53 | 3.49 ± 1.05 | 2.83 ± 0.81 | 1.33 ± 0.49 | |
Femur | 1.67 ± 0.61 | 1.81 ± 0.44 | 1.58 ± 0.28 | 1.55 ± 0.49 | 1.05 ± 0.36 | |
HuIgG | Blood | 15.99 ± 1.99 | 14.81 ± 1.14 | 14.68 ± 2.59 | 11.20 ± 2.02 | 11.30 ± 1.59 |
Tumor | 7.51 ± 1.98 | 7.41 ± 0.73 | 5.70 ± 0.96 | 5.06 ± 1.89 | 7.68 ± 2.16 | |
Liver | 6.33 ± 1.61 | 6.21 ± 0.77 | 7.35 ± 0.74 | 6.14 ± 2.43 | 5.32 ± 0.82 | |
Spleen | 5.63 ± 0.86 | 5.74 ± 1.39 | 5.83 ± 1.08 | 9.88 ± 8.79 | 6.56 ± 1.56 | |
Kidney | 6.00 ± 0.87 | 6.04 ± 0.21 | 5.86 ± 0.83 | 3.84 ± 1.72 | 4.75 ± 0.78 | |
Lung | 7.59 ± 0.56 | 7.09 ± 0.22 | 6.22 ± 2.19 | 4.88 ± 1.23 | 5.58 ± 1.24 | |
Heart | 6.40 ± 1.09 | 5.06 ± 0.78 | 4.69 ± 0.87 | 3.73 ± 0.53 | 3.56 ± 0.58 | |
Femur | 2.09 ± 0.16 | 1.98 ± 0.25 | 1.41 ± 0.69 | 2.19 ± 1.16 | 1.59 ± 0.35 |
3.3. Evaluation of 177Lu-Trastuzumab for Targeting Intraperitoneal Tumor Burden
177Lu-Trastuzumab | 177Lu-HuIgG | |||||
---|---|---|---|---|---|---|
Tissue | 24 h | 72 h | 24 h | 72 h | ||
Blood | 10.47 ± 9.19 | 10.15 ± 6.27 | 16.8 ± 2.60 | 5.13 ± 3.17 | ||
Tumor | 13.44 ± 11.52 | 31.70 ± 16.20 | 5.84 ± 1.27 | 5.52 ± 4.92 | ||
Liver | 4.83 ± 3.63 | 6.11 ± 3.33 | 6.76 ± 1.01 | 2.95 ± 2.06 | ||
Spleen | 6.81 ± 5.66 | 10.63 ± 6.37 | 6.67 ± 1.17 | 4.22 ± 2.42 | ||
Kidney | 4.46 ± 3.45 | 5.05 ± 1.69 | 7.07 ± 1.25 | 2.46 ± 1.29 | ||
Lungs | 4.81 ± 3.84 | 4.30 ± 2.17 | 7.48 ± 1.70 | 2.28 ± 1.24 | ||
Heart | 3.60 ± 2.97 | 3.59 ± 1.80 | 6.01 ± 1.23 | 1.70 ± 1.03 | ||
Femur | 1.96 ± 1.58 | 2.54 ± 1.05 | 2.72 ± 0.68 | 1.19 ± 0.62 |
3.4. Validation of 177Lu-Trastuzumab as a Radioimmunotherapeutic and Determination of an Effective Therapeutic Dose
Dose (μCi) | Treatment | ||||
---|---|---|---|---|---|
None | Trastuzumab | HuIgG | |||
Median Survival(d) | Median Survival(d) | Therapeutic Index | Median Survival(d) | Therapeutic Index | |
0 | 10 | ||||
125 | 46 | 4.6 | 14 | 1.4 | |
250 | 91 | 9.1 | --- | --- | |
375 | 124.5 | 12.45 | 31 | 3.1 | |
500 | 69.5 | 6.95 | --- | --- | |
750 | 17 | 1.7 | 16 | 1.6 |
3.5. Validation of Tumor Targeting with 177Lu-Trastuzumab by Planar γ-Scintigraphy
4. Conclusions
Conflict of Interest
Acknowledgements
References
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Ray, G.L.; Baidoo, K.E.; Keller, L.M.M.; Albert, P.S.; Brechbiel, M.W.; Milenic, D.E. Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease. Pharmaceuticals 2012, 5, 1-15. https://doi.org/10.3390/ph5010001
Ray GL, Baidoo KE, Keller LMM, Albert PS, Brechbiel MW, Milenic DE. Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease. Pharmaceuticals. 2012; 5(1):1-15. https://doi.org/10.3390/ph5010001
Chicago/Turabian StyleRay, Geoffrey L., Kwamena E. Baidoo, Lanea M. M. Keller, Paul S. Albert, Martin W. Brechbiel, and Diane E. Milenic. 2012. "Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease" Pharmaceuticals 5, no. 1: 1-15. https://doi.org/10.3390/ph5010001