Preclinical Pharmacokinetics, Tolerability, and Pharmacodynamics of Metuzumab, a Novel CD147 Human–Mouse Chimeric and Glycoengineered Antibody

Zhang, Zheng; Zhang, Yang; Sun, Qian; Fěng, Fang; Huhe, Muren; Li, Mi; Chen, Zhi‐Nan

doi:10.1158/1535-7163.mct-14-0104

Cited by 28 publications

(38 citation statements)

References 43 publications

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“…Our previously study demonstrated that metuzumab is a nonfucosylate antibody, and promote antibody-dependent cellular cytotoxicity (ADCC) efficacy in vivo , 22 however, in this study, we found metuzumab apparently enhanced the antitumor efficacy of GP, but not satisfied to that of NP or TP. We speculated metuzumab enhanced chemosensitivity of NSCLC cells to GP is not simply due to ADCC effect, nor cisplatin.…”

Section: Resultscontrasting

confidence: 86%

“…Metuzumab is an affinity-optimized and nonfucosylated anti-CD147 human-mouse chimeric IgG1 monoclonal antibody designed to reduce immunoreactivity and enhance antibody-dependent cell-mediated cytotoxicity (ADCC). 22 It has been approved to perform phase I clinical trial for NSCLC in China by China Food and Drug Administration (CFDA). Earlier pre-clinical studies of metuzumab combined with cisplatin and gemcitabine in xenograft mouse have demonstrated that this combination therapy was safe, tolerable and effectiveness.…”

Section: Introductionmentioning

confidence: 99%

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Metuzumab enhanced chemosensitivity and apoptosis in non-small cell lung carcinoma

Fěng

Wang

Sun

et al. 2017

Cancer Biology & Therapy

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Targeted therapeutics is used as an alternative treatment of non-small cell lung cancer (NSCLC); however, treatment effect is far from being satisfactory, and therefore identification of new targets is needed. We have previously shown that metuzumab inhibit tumor growth in vivo. The present study was performed to investigate the anti-tumor efficacy of metuzumab combined with gemcitabine and cisplatin (GP), paclitaxel and cisplatin (TP) or navelbine and cisplatin (NP) regimens in multiple NSCLC cell lines. Our results demonstrate that, in comparison to single agent metuzumab or GP treated cells, metuzumab combined with GP display inhibitory effects on tumor growth. Furthermore, we found that metuzumab elevated the sensitivity of cell lines to gemcitabine, which was identified by MTT assay. Flow cytometric analysis showed that metuzumab combined with gemcitabine (GEM) treatment led to an obvious G1 arrest and an elevated apoptosis in A549, NCI-H460 and NCI-H520 cells. Western blot analysis also demonstrated a significantly reduced level of cyclin D1, Bcl-2, and an obviously increase level of Bax and full-length caspase-3 in A549, NCI-H460 and NCI-H520 cells treated with metuzumab/gemcitabine combination in comparison with single agent treated cells. In addition, metuzumab/gemcitabine treated A549, NCI-H460 and NCI-H520 cells also demonstrated a significantly increase in deoxycytidine kinase (dCK) protein level compared with single agent metuzumab or gemcitabine treated cells. Xenograft models also demonstrated that this metuzumab/gemcitabine combination led to upregulation of dCK. Taken together, the mechanisms of metuzumab combined with GP repress tumor growth were that the combined treatment significantly inhibited the tumor cell proliferation, apoptosis and cell cycle in vitro and in vivo and at least partially by induction of dCK expression. Our results suggested that metuzumab could significantly enhance chemosensitivity of human NSCLC cells to gemcitabine. Metuzumab/gemcitabine combination treatment may be a potentially useful therapeutic regimen for NSCLC patients.

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Section: Resultscontrasting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Metuzumab enhanced chemosensitivity and apoptosis in non-small cell lung carcinoma

Fěng

Wang

Sun

et al. 2017

Cancer Biology & Therapy

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“…NSC23925b also showed high volumes of distribution at a steady state (>9 L/kg). The demonstrated concentration-time profiles were analogous to some reported drug resistance inhibitors 25 26 27 . The peak plasma inhibitor concentrations were observed at the earliest time point especially after I.V.…”

Section: Discussionsupporting

confidence: 73%

Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats

Gao

Shen

Choy

et al. 2016

Sci Rep

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Overexpression of P-glycoprotein (Pgp) increases multidrug resistance (MDR) in cancer, which greatly impedes satisfactory clinical treatment and outcomes of cancer patients. Due to unknown pharmacokinetics, the use of Pgp inhibitors to overcome MDR in the clinical setting remains elusive despite promising in vitro results. The purpose of our current preclinical study is to investigate the pharmacokinetics and tolerability of NSC23925b, a novel and potent P-glycoprotein inhibitor, in rodents. Plasma pharmacokinetic studies of single-dose NSC23925b alone or in combination with paclitaxel or doxorubicin were conducted in male BALB/c mice and Sprague-Dawley rats. Additionally, inhibition of human cytochrome P450 (CYP450) by NSC23925b was examined in vitro. Finally, the maximum tolerated dose (MTD) of NSC23925b was determined. NSC23925b displayed favorable pharmacokinetic profiles after intraperitoneal/intravenous (I.P./I.V.) injection alone or combined with chemotherapeutic drugs. The plasma pharmacokinetic characteristics of the chemotherapy drugs were not affected when co-administered with NSC23925b. All the animals tolerated the I.P./I.V. administration of NSC23925b. Moreover, the enzymatic activity of human CYP450 was not inhibited by NSC23925b. Our results demonstrated that Pgp inhibitor NSC23925b exhibits encouraging preclinical pharmacokinetic characteristics and limited toxicity in vivo. NSC23925b has the potential to treat cancer patients with MDR in the future.

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“…Clinically, anti-CD147 antibody alone has proven to suppress primary tumor growth and hepatocellular carcinoma metastasis (Wang et al, 2015, Zhang et al, 2015). While these anti-tumor efficacies were largely attribute to tumor-specific targeting and blocking of CD147 function in tumor cells, we hypothesized that CD147 may also serve as a modulatory target to reprogram T cells into superior NK-like cytotoxic cells, which may be a complimentary mechanism for the therapeutic effect of anti-CD147 blocking.…”

Section: Resultsmentioning

confidence: 99%

Targeting CD147 for T to NK Lineage Reprogramming and Tumor Therapy

et al. 2017

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CD147 is highly expressed on the surface of numerous tumor cells to promote invasion and metastasis. Targeting these cells with CD147-specific antibodies has been validated as an effective approach for lung and liver cancer therapy. In the immune system, CD147 is recognized as a co-stimulatory receptor and impacts the outcome of thymic selection. Using T cell-specific deletion, we showed here that in thymus CD147 is indispensable for the stable αβ T cell lineage commitment: loss of CD147 biases both multipotent DN (double negative) and fully committed DP (double positive) cells into innate NK-like lineages. Mechanistically, CD147 deficiency results in impaired Wnt signaling and expression of BCL11b, a master transcription factor in determining T cell identity. In addition, functional blocking of CD147 by antibody phenocopies genetic deletion to enrich NK-like cells in the periphery. Furthermore, using a melanoma model and orthotopic liver cancer transplants, we showed that the augmentation of NK-like cells strongly associates with resistance against tumor growth upon CD147 suppression. Therefore, besides its original function in tumorigenesis, CD147 is also an effective surface target for immune modulation in tumor therapy.

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Preclinical Pharmacokinetics, Tolerability, and Pharmacodynamics of Metuzumab, a Novel CD147 Human–Mouse Chimeric and Glycoengineered Antibody

Cited by 28 publications

References 43 publications

Metuzumab enhanced chemosensitivity and apoptosis in non-small cell lung carcinoma

Metuzumab enhanced chemosensitivity and apoptosis in non-small cell lung carcinoma

Pharmacokinetics and tolerability of NSC23925b, a novel P-glycoprotein inhibitor: preclinical study in mice and rats

Targeting CD147 for T to NK Lineage Reprogramming and Tumor Therapy

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