Novel EphB4 Monoclonal Antibodies Modulate Angiogenesis and Inhibit Tumor Growth

Krasnoperov, Valery; Kumar, Sunil; Ley, Eric J.; Li, Xiuqing; Scehnet, Jeffrey S.; Liu, Ren; Zozulya, Sergey; Gill, Parkash S.

doi:10.2353/ajpath.2010.090755

Cited by 78 publications

(78 citation statements)

References 31 publications

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“…sEphB4 was shown to antagonize forward and reverse signaling of EphrinB2, reduce vessel density and inhibit xenograft tumor growth (48). Anti-EphB4 antibody inhibited tumor angiogenesis and growth alone and in combination with bevacizumab (49). Combined therapy of sEphB4 with soluble DLL4 displayed cumulative efficacy against mouse insulinoma growth (50).…”

Section: Discussionmentioning

confidence: 99%

DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo

Sainson²,

Oon³

et al. 2011

Cancer Research

213

187

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Resistance to VEGF inhibitors is emerging as a major clinical problem. Notch signaling has been implicated in tumor angiogenesis. Therefore, to investigate mechanisms of resistance to angiogenesis inhibitors, we transduced human glioblastoma cells with retroviruses encoding Notch delta-like ligand 4 (DLL4), grew them as tumor xenografts and then treated the murine hosts with the VEGF-A inhibitor bevacizumab. We found that DLL4-mediated tumor resistance to bevacizumab in vivo. The large vessels induced by DLL4-Notch signaling increased tumor blood supply and were insensitive to bevacizumab. However, blockade of Notch signaling by dibenzazepine, a g-secretase inhibitor, disrupted the large vessels and abolished the tumor resistance. Multiple molecular mechanisms of resistance were shown, including decreased levels of hypoxiainduced VEGF and increased levels of the VEGF receptor VEGFR1 in the tumor stroma, decreased levels of VEGFR2 in large blood vessels, and reduced levels of VEGFR3 overall. DLL4-expressing tumors were also resistant to a VEGFR targeting multikinase inhibitor. We also observed activation of other pathways of tumor resistance driven by DLL4-Notch signaling, including the FGF2-FGFR and EphB4-EprinB2 pathways, the inhibition of which reversed tumor resistance partially. Taken together, our findings show the importance of classifying mechanisms involved in angiogenesis in tumors, and how combination therapy to block DLL4-Notch signaling may enhance the efficacy of VEGF inhibitors, particularly in DLL4-upregulated tumors, and thus provide a rational base for the development of novel strategies to overcome antiangiogenic resistance in the clinic. Cancer Res; 71(18); 6073-83. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo

Sainson²,

Oon³

et al. 2011

Cancer Research

213

187

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“…In contrast, hAb47 does not internalize after binding to the receptor (17). In the HT29 tumor model, 64 Cu-DOTA-Lys-hAb131 demonstrated significantly higher tumor uptake (21.90 6 1.93 and 29.48 6 2.60 %ID/g at 24 and 48 h after injection, respectively) than did 64 Cu-DOTALys-hAb47 (16.00 6 1.88 and 18.13 6 1.73 %ID/g at 24 and 48 h after injection, respectively; P 5 0.019 and 0.003, respectively) (Figs.…”

Section: Small-animal Pet Imaging Of Ephb4mentioning

confidence: 99%

“…Moreover, the antibody-based imaging probes would be more suitable for patient screening as they are closely related to the antibody drug to be used in immunotherapy. In this study, we developed a series of EphB4-targeted PET probes based on 2 anti-EphB4 monoclonal antibodies, hAb47 and hAb131 (17).…”

Section: Discussionmentioning

confidence: 99%

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PET Imaging of Colorectal and Breast Cancer by Targeting EphB4 Receptor with⁶⁴Cu-Labeled hAb47 and hAb131 Antibodies

Liu

Park

et al. 2013

J Nucl Med

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Accumulating evidence suggests that ephrin type B receptor 4 (EphB4) plays a key role in the progression of numerous cancer types. In this study, we developed a series of 64 Cu-labeled antibodies for PET imaging of tumor EphB4 expression. Methods: Anti-EphB4 antibodies (hAb47 and hAb131) were conjugated with the 64 Cu-chelator DOTA through lysine, cysteine, or oligosaccharide on the antibody. DOTA-human IgG (hIgG) was also prepared as a control, which did not bind to EphB4. The EphB4 binding activity of these probes was evaluated through the bead-based binding assay with EphB4-alkaline phosphatase. The resulting PET probes were further evaluated in both HT29 (colorectal cancer) and MDA-MB-231 (breast cancer) xenografts. Results: All 3 conjugation methods retained most of the EphB4 binding activity of the antibodies (83.85% 6 3.82%, 76.25% 6 5.90%, 98.93% 6 3.75%, and 82.09% 6 4.14% for DOTA-Lys-hAb47, DOTA-Cys-hAb47, DOTASug-hAb47, and DOTA-Lys-hAb131, respectively). Although DOTASug-hAb47 demonstrated the highest receptor binding activity based on a EphB4 binding assay, the corresponding PET probe was trapped in the liver quickly in vivo. In HT29 xenografts, both 64 Cu-DOTA-Lys-hAb47 and 64 Cu-DOTA-Cys-hAb47 demonstrated prominent tumor accumulation, which reached a maximum at 48 h after injection (18.13 6 1.73 percentage injected dose [%ID]/g and 11.81 6 2.05 %ID/g, respectively). In contrast, 64 Cu-DOTA-LyshIgG had a low tumor accumulation, thus demonstrating the target specificity of EphB4-antibody-based probes. Moreover, 64 Cu-DOTA-Lys-hAb131 (29.48 6 2.60 %ID/g) demonstrated significantly higher HT29 tumor accumulation than 64 Cu-DOTA-Lys-hAb47. 64 Cu-DOTA-Lys-hAb131 was also found to specifically accumulate in the MDA-MB-231 tumor model (12.96 6 2.31 %ID/g). Conclusion: We have demonstrated that EphB4 can serve as a valid target for colorectal and breast cancer imaging. This approach would be valuable for evaluating disease course and therapeutic efficacy at the earliest stages of anti-EphB4 treatment. Moreover, these newly developed probes may have important applications in other cancer types overexpressing EphB4.

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“…Therapeutic target in leukaemia and glioblastoma 59,146 EphA7 Tumour suppressor in T-LBL and follicular lymphoma 84,156 EphB4 EphB4 antibody to inhibit solid tumour growth 151 In summary, the aberrant expression of Eph receptors in haematopoietic tumours reflects the spectrum of functions of these receptors in all cancers. In some cancers these genes act as tumour suppressor, examples being EphA1 in colorectal cancer and EphA7 in follicular lymphomas.…”

Section: Epha3mentioning

confidence: 99%

The role of Eph proteins in haematopoiesis and leukaemia

Charmsaz¹

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When HSCs from wild type mice were transduced with the MLL-AF9 retrovirus and engrafted into recipient mice, the subsequent leukaemias showed significant expression of EphA2 on leukemic blast cells. However when EphA2 null HSCs were engrafted, the absence of EphA2 appeared to have no effect on the leukemic process, demonstrating that EphA2 is not essential for leukaemia progression. Analysis showing increased expression of EphA7 and other Eph proteins demonstrate a possible compensatory role for the lack EphA2 expression, if Eph signalling was required for leukemic evolution in this model. Following these observations, the role iii of EphA2 as a therapeutic target for MLL-AF9 leukaemia was evaluated. Results showed that radiolabelled (beta particle-emitting lutetium) EphA2 was an effective therapeutic approach by significantly delaying the progression of MLL-AF9 leukaemia. Given the poor prognosis of MLL-driven paediatric acute lymphoblastic leukaemia (ALL) this data raises the prospect of effective EphA2-targeted therapy for this disease.EphA3 is another member of the Eph/ephrin family of RTKs, which was originally described in leukaemia and has subsequently been described in many other different cancers including sarcomas, lung cancer, melanoma and glioblastoma. The EphA3-specific monoclonal antibody, IIIA4, binds and activates both human and mouse

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Novel EphB4 Monoclonal Antibodies Modulate Angiogenesis and Inhibit Tumor Growth

Cited by 78 publications

References 31 publications

DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo

DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo

PET Imaging of Colorectal and Breast Cancer by Targeting EphB4 Receptor with⁶⁴Cu-Labeled hAb47 and hAb131 Antibodies

The role of Eph proteins in haematopoiesis and leukaemia

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Novel EphB4 Monoclonal Antibodies Modulate Angiogenesis and Inhibit Tumor Growth

Cited by 78 publications

References 31 publications

DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo

DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo

PET Imaging of Colorectal and Breast Cancer by Targeting EphB4 Receptor with64Cu-Labeled hAb47 and hAb131 Antibodies

The role of Eph proteins in haematopoiesis and leukaemia

Contact Info

Product

Resources

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PET Imaging of Colorectal and Breast Cancer by Targeting EphB4 Receptor with⁶⁴Cu-Labeled hAb47 and hAb131 Antibodies