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A Two-Step Pretargeted Nanotherapy for CD20 Crosslinking May Achieve Superior Anti-Lymphoma Efficacy to Rituximab.

Chu TW, Zhang R, Yang J, Chao MP, Shami PJ, Kopeček J - Theranostics (2015)

Bottom Line: Consecutive treatment with the two components resulted in CD20 clustering on the cell surface and effectively killed malignant B-cells in vivo.In a mouse model of human non-Hodgkin lymphoma (NHL), increasing the time lag from 1 h to 5 h resulted in dramatically improved tumor growth inhibition and animal survival.In summary, our approach may constitute a novel treatment for NHL and other B-cell malignancies with significant advantages over conventional chemo-immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.

ABSTRACT
The use of rituximab, an anti-CD20 mAb, in combination with chemotherapy is the current standard for the treatment of B-cell lymphomas. However, because of a significant number of treatment failures, there is a demand for new, improved therapeutics. Here, we designed a nanomedicine that crosslinks CD20 and directly induces apoptosis of B-cells without the need for toxins or immune effector functions. The therapeutic system comprises a pretargeting component (anti-CD20 Fab' conjugated with an oligonucleotide1) and a crosslinking component (N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer grafted with multiple complementary oligonucleotide2). Consecutive treatment with the two components resulted in CD20 clustering on the cell surface and effectively killed malignant B-cells in vivo. To enhance therapeutic efficacy, a two-step pretargeting approach was employed. We showed that the time lag between the two doses can be optimized based on pharmacokinetics and biodistribution of the Fab'-oligonucleotide1 conjugate. In a mouse model of human non-Hodgkin lymphoma (NHL), increasing the time lag from 1 h to 5 h resulted in dramatically improved tumor growth inhibition and animal survival. When the 5 h interval was used, the nanotherapy was more efficacious than rituximab and led to complete eradication of lymphoma cells with no signs of metastasis or disease recurrence. We further evaluated the nanomedicine using patient mantle cell lymphoma cells; the treatment demonstrated more potent apoptosis-inducing activity than rituximab hyper-crosslinked with secondary antibodies. In summary, our approach may constitute a novel treatment for NHL and other B-cell malignancies with significant advantages over conventional chemo-immunotherapy.

No MeSH data available.


Related in: MedlinePlus

Three-dimensional microcomputed tomography (microCT) analysis. Mice were intravenously injected with Raji-luc cells and exposed to different treatments as in Fig. 4. Imaging was performed on day 70 and focused on the lumbar spine and hind limbs. Bone destruction, as a result of lymphoma metastasis, is indicated by the red arrow. Bioluminescence images (day 35) of the same mice are shown in the bottom right corner for comparison.
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Figure 5: Three-dimensional microcomputed tomography (microCT) analysis. Mice were intravenously injected with Raji-luc cells and exposed to different treatments as in Fig. 4. Imaging was performed on day 70 and focused on the lumbar spine and hind limbs. Bone destruction, as a result of lymphoma metastasis, is indicated by the red arrow. Bioluminescence images (day 35) of the same mice are shown in the bottom right corner for comparison.

Mentions: We also performed three-dimensional microcomputed tomography (3D microCT) imaging on the mice that bore Raji-luc lymphoma xenografts and underwent different treatments (Fig. 5). These images were focused on the lumbar spine and hind limbs (hot-spots of B-cell NHL metastasis). Results revealed extensive bone destruction in the rituximab-treated mice and moderate bone lesions in the mice administered drug-free nanotherapeutics using the 1 h interval (Cons 1h). Observed bone heterogeneity was extensive in the femur, and in some cases, the proximal tibia (close to the knee joint), indicating abnormal osteoclast activation (bone remodeling) stimulated by lymphoma metastases 32. However, no signs of bone remodeling were found in mice treated with Cons 5h. Taken together, superior anti-lymphoma efficacy was achieved using the 5 h interval treatment, when compared to the 1 h treatment and rituximab. These results validate our hypothesis that 5 h is optimal for efficient pretargeting/2nd-step targeting in drug-free macromolecular therapeutics.


A Two-Step Pretargeted Nanotherapy for CD20 Crosslinking May Achieve Superior Anti-Lymphoma Efficacy to Rituximab.

Chu TW, Zhang R, Yang J, Chao MP, Shami PJ, Kopeček J - Theranostics (2015)

Three-dimensional microcomputed tomography (microCT) analysis. Mice were intravenously injected with Raji-luc cells and exposed to different treatments as in Fig. 4. Imaging was performed on day 70 and focused on the lumbar spine and hind limbs. Bone destruction, as a result of lymphoma metastasis, is indicated by the red arrow. Bioluminescence images (day 35) of the same mice are shown in the bottom right corner for comparison.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4440441&req=5

Figure 5: Three-dimensional microcomputed tomography (microCT) analysis. Mice were intravenously injected with Raji-luc cells and exposed to different treatments as in Fig. 4. Imaging was performed on day 70 and focused on the lumbar spine and hind limbs. Bone destruction, as a result of lymphoma metastasis, is indicated by the red arrow. Bioluminescence images (day 35) of the same mice are shown in the bottom right corner for comparison.
Mentions: We also performed three-dimensional microcomputed tomography (3D microCT) imaging on the mice that bore Raji-luc lymphoma xenografts and underwent different treatments (Fig. 5). These images were focused on the lumbar spine and hind limbs (hot-spots of B-cell NHL metastasis). Results revealed extensive bone destruction in the rituximab-treated mice and moderate bone lesions in the mice administered drug-free nanotherapeutics using the 1 h interval (Cons 1h). Observed bone heterogeneity was extensive in the femur, and in some cases, the proximal tibia (close to the knee joint), indicating abnormal osteoclast activation (bone remodeling) stimulated by lymphoma metastases 32. However, no signs of bone remodeling were found in mice treated with Cons 5h. Taken together, superior anti-lymphoma efficacy was achieved using the 5 h interval treatment, when compared to the 1 h treatment and rituximab. These results validate our hypothesis that 5 h is optimal for efficient pretargeting/2nd-step targeting in drug-free macromolecular therapeutics.

Bottom Line: Consecutive treatment with the two components resulted in CD20 clustering on the cell surface and effectively killed malignant B-cells in vivo.In a mouse model of human non-Hodgkin lymphoma (NHL), increasing the time lag from 1 h to 5 h resulted in dramatically improved tumor growth inhibition and animal survival.In summary, our approach may constitute a novel treatment for NHL and other B-cell malignancies with significant advantages over conventional chemo-immunotherapy.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.

ABSTRACT
The use of rituximab, an anti-CD20 mAb, in combination with chemotherapy is the current standard for the treatment of B-cell lymphomas. However, because of a significant number of treatment failures, there is a demand for new, improved therapeutics. Here, we designed a nanomedicine that crosslinks CD20 and directly induces apoptosis of B-cells without the need for toxins or immune effector functions. The therapeutic system comprises a pretargeting component (anti-CD20 Fab' conjugated with an oligonucleotide1) and a crosslinking component (N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer grafted with multiple complementary oligonucleotide2). Consecutive treatment with the two components resulted in CD20 clustering on the cell surface and effectively killed malignant B-cells in vivo. To enhance therapeutic efficacy, a two-step pretargeting approach was employed. We showed that the time lag between the two doses can be optimized based on pharmacokinetics and biodistribution of the Fab'-oligonucleotide1 conjugate. In a mouse model of human non-Hodgkin lymphoma (NHL), increasing the time lag from 1 h to 5 h resulted in dramatically improved tumor growth inhibition and animal survival. When the 5 h interval was used, the nanotherapy was more efficacious than rituximab and led to complete eradication of lymphoma cells with no signs of metastasis or disease recurrence. We further evaluated the nanomedicine using patient mantle cell lymphoma cells; the treatment demonstrated more potent apoptosis-inducing activity than rituximab hyper-crosslinked with secondary antibodies. In summary, our approach may constitute a novel treatment for NHL and other B-cell malignancies with significant advantages over conventional chemo-immunotherapy.

No MeSH data available.


Related in: MedlinePlus