Antiangiogenic chimeric anti-endoglin (CD105) antibody: pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin

Shiozaki, Ken; Harada, Naoko; Greco, William R.; Haba, Akinao; Uneda, Shima; Tsai, Hilda; Seon, Ben K.

doi:10.1007/s00262-005-0691-4

Cited by 31 publications

(28 citation statements)

References 33 publications

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“…To facilitate clinical application of the anti-EDG mAbs, we generated a recombinant human/mouse chimeric mAb termed c-SN6j from SN6j. A dose escalation study of c-SN6j was performed in non-human primates to evaluate the pharmacokinetic parameters, immunogenicity and potential toxicity of c-SN6j (33). The results are very encouraging.…”

Section: Discussionmentioning

confidence: 90%

Effective anti-angiogenic therapy of established tumors in mice by naked anti-human endoglin (CD105) antibody: Differences in growth rate and therapeutic response between tumors growing at different sites

Tsujie

Uneda²,

Tsai³

et al. 2006

Int J Oncol

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Abstract. We investigated anti-angiogenic/vascular targeting therapy of established tumors in immunocompetent mice using an anti-human endoglin (EDG; CD105) monoclonal antibody (mAb) SN6j. SN6j weakly cross-reacted with murine endothelial cells but reacted neither with colon-26 murine colon carcinoma cells nor with 4T1 murine mammary carcinoma cells. Systemic administration of naked (unconjugated) SN6j showed significant growth suppression of established tumors of colon-26 and 4T1 cells in immunocompetent BALB/c mice (P<0.05). Moreover, the overall survival rate of SN6j-treated mice was significantly higher than that of control IgG-treated mice (P<0.01). During these studies, we found that two different types of tumor formed in BALB/c and immunodeficient SCID mice when three different types of tumor cells (colon-26, 4T1 and MCF-7 human breast cancer cells) were inoculated subcutaneously. One type of tumor grew in the skin-side tissue (i.e., epidermis, corium, or subcutis), and mainly invaded into the corium and epidermis. The other type grew in the muscle-side tissue (i.e., fascia, muscle, or peritoneum/pleura). We termed the former SS tumors and the latter MS tumors. MS tumors grew faster than SS tumors. This differential growth of MS and SS tumors was observed in three different animal models, i.e., colon-26 tumors and 4T1 tumors in BALB/c mice, and MCF-7 tumors in SCID mice. In the therapeutic study of colon-26 and 4T1 tumors with SN6j, MS tumors were less responsive to therapy than SS tumors although SN6j showed significant antitumor efficacy against both tumors (P<0.05). The results show that antitumor therapy can yield different therapeutic outcomes depending on the tumor growth sites even for the same tumor. A differential survival between mice with the two types of tumor was also observed when mice were untreated (P<0.01).

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Section: Discussionmentioning

confidence: 90%

Effective anti-angiogenic therapy of established tumors in mice by naked anti-human endoglin (CD105) antibody: Differences in growth rate and therapeutic response between tumors growing at different sites

Tsujie

Uneda²,

Tsai³

et al. 2006

Int J Oncol

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“…It is known that angiogenesis is crucial for tumour development and progression. Recent evidence showed that selected anti-CD105 monoclonal antibodies (mAbs) significantly inhibited the proliferation of cultured human microvascular and macrovascular endothelial cells [6], and in mouse models, certain anti-CD105 mAbs and their immuno-conjugates (conjugates with deglycosylated ricin A-chain or with 125 I) induced regression/ suppression of established tumours and inhibited growth of pre-established tumours [15]. These results support the notion that CD105 is a promising vascular target to implement innovative antibody-based therapeutic strategies in human cancer.…”

Section: Resultsmentioning

confidence: 99%

Endoglin expression is associated with poor oncologic outcome in oral and oropharyngeal carcinoma

Marioni

Marino

Giacomelli

et al. 2006

Acta Oto-Laryngologica

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The mean MVDs were 3.6 and 3.1 in pN+ and pN0 groups, respectively (p>0.05). The mean CD105-assessed MVDs were 4.7 in the group with locoregional recurrence and 2.9 in the group without locoregional recurrence or post-treatment diagnosis of distant metastasis (p=0.01). The mean CD105-assessed MVD in primary oral and oropharyngeal SCCs with poor oncological outcome (recurrence of disease or occurrence of distant metastasis) was 4.3. The mean MVD in primary oral and oropharyngeal SCCs with good outcome was 2.9. Statistical analysis showed a significant difference between CD105-assessed MVD in poor and good outcome groups (p=0.02).

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“…TRC105 concentration was determined using a validated enzyme-linked immunosorbent assay (ELISA) with a limit of quantitation of 78 ng/mL (33). …”

Section: Methodsmentioning

confidence: 99%

An Open-Label Phase Ib Dose-Escalation Study of TRC105 (Anti-Endoglin Antibody) with Bevacizumab in Patients with Advanced Cancer

Gordon

Robert

Matei

et al. 2014

Clinical Cancer Research

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Purpose Endoglin, an endothelial cell membrane receptor expressed on angiogenic tumor vessels, is essential for angiogenesis and upregulated in the setting of VEGF inhibition. TRC105 is an anti-endoglin IgG1 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, pharmacokinetics, and anti-tumor activity of TRC105 in combination with bevacizumab. Patients and Methods Patients (n=38) with advanced solid tumors, Eastern Cooperative Group performance status 0–1, and normal organ function were treated with escalating doses of TRC105 plus bevacizumab until disease progression or unacceptable toxicity using a standard 3 + 3 phase 1 design. Results TRC105 and bevacizumab were well tolerated at their recommended single agent doses (10 mg/kg) when the initial dose of TRC105 was delayed by one week and divided over two days to limit the frequency of headache. The concurrent administration of bevacizumab and TRC105 did not otherwise potentiate known toxicities of TRC105 or bevacizumab. Hypertension and proteinuria were observed, though not at rates expected for single agent bevacizumab. Several patients who had previously progressed on bevacizumab or VEGF receptor tyrosine kinase inhibitor (VEGFR TKI) treatment experienced reductions in tumor volume, including two partial responses by RECIST, and six remained without progression for longer periods than during their prior VEGF inhibitor therapy. Conclusion TRC105 was well tolerated with bevacizumab and clinical activity was observed in a VEGF inhibitor refractory population. Ongoing clinical trials are testing TRC105 in combination with bevacizumab in glioblastoma, and with VEGFR TKIs in renal cell carcinoma, hepatocellular carcinoma, and soft tissue sarcoma.

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Antiangiogenic chimeric anti-endoglin (CD105) antibody: pharmacokinetics and immunogenicity in nonhuman primates and effects of doxorubicin

Cited by 31 publications

References 33 publications

Effective anti-angiogenic therapy of established tumors in mice by naked anti-human endoglin (CD105) antibody: Differences in growth rate and therapeutic response between tumors growing at different sites

Effective anti-angiogenic therapy of established tumors in mice by naked anti-human endoglin (CD105) antibody: Differences in growth rate and therapeutic response between tumors growing at different sites

Endoglin expression is associated with poor oncologic outcome in oral and oropharyngeal carcinoma

An Open-Label Phase Ib Dose-Escalation Study of TRC105 (Anti-Endoglin Antibody) with Bevacizumab in Patients with Advanced Cancer

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