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Anti-cancer Antibody Trastuzumab-Melanotransferrin Conjugate (BT2111) for the Treatment of Metastatic HER2+ Breast Cancer Tumors in the Brain: an In-Vivo Study

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Abstract

Purpose

The ability of human melanotransferrin (hMTf) to carry a therapeutic concentration of trastuzumab (BTA) in the brain after conjugation (in the form of trastuzumab-melanotransferrin conjugate, BT2111 conjugate) was investigated by measuring the reduction of the number and size of metastatic human HER2+ breast cancer tumors in a preclinical model of brain metastases of breast cancer.

Methods

Human metastatic brain seeking breast cancer cells were injected in NuNu mice (n = 6–12 per group) which then developed experimental brain metastases. Drug uptake was analyzed in relation to metastasis size and blood-tumor barrier permeability. To investigate in-vivo activity against brain metastases, equimolar doses of the conjugate, and relevant controls (hMTf and BTA) in separate groups were administered biweekly after intracardiac injection of the metastatic cancer cells.

Results

The trastuzumab-melanotransferrin conjugate (BT2111) reduced the number of preclinical human HER2+ breast cancer metastases in the brain by 68% compared to control groups. Tumors which remained after treatment were 46% smaller than the control groups. In contrast, BTA alone had no effect on reducing number of metastases, and was associated with only a minimal reduction in metastasis size.

Conclusions

The results suggest the novel trastuzumab-melanotransferrin conjugate (BT2111) may have utility in treating brain metastasis and validate hMTf as a potential vector for antibody transport across the Blood Brain Barrier (BBB).

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Abbreviations

BBB:

Blood brain barrier

BDT:

Brain distant to tumor

BT2111 BTA-MTf:

Antibody trastuzumab-melanotransferrin conjugate

BTA:

Trastuzumab

BTB:

Blood tumor barrier

CT:

Computed tomography

ER:

Estrogen receptor

FDA:

Food and drug administration

HER2 HER-2/neu or c-erbB-2:

Human epidermal growth factor receptor 2

hMTf:

human Melanotransferrin

Kin :

Drug uptake

LRP:

Low density lipoprotein receptor related protein

MDA-MB-231-Her2:

Metastatic brain seeking breast cancer cells

MNF:

Anti-cytokeratin mouse monoclonal IgG antibody

MRI:

Magnetic resonance imaging

p97:

Melanoma tumor antigen

PBS:

Phosphate buffered saline

Tf:

Transferrin

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ACKNOWLEDGMENTS AND DISCLOSURES

This research was supported by grants from the National Cancer Institute (R01CA166067-01A1), Department of Defense Breast Cancer Research Program (W81XWH-062-0033), and BiOasis awarded to P. Lockman. Additional support for this research was provided through the National Institute of General Medical Sciences of the National Institutes of Health (CTSI Award: U54GM104942, and the CoBRE P30 GM103488).

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    Authors and Affiliations

    1. School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA

      Mohamed Ismail Nounou, Chris E. Adkins, Tori B. Terrell-Hall & Mohamed Afroz

    2. Department of Pharmaceutics, School of Pharmacy, Alexandria University, Alexandria, 21521, Egypt

      Mohamed Ismail Nounou

    3. Department of Pharmaceutical Sciences, Appalachian College of Pharmacy, Oakwood, Virginia, 24631, USA

      Mohamed Ismail Nounou

    4. School of Pharmacy, West Virginia University Health Sciences Center, Morgantown, West Virginia, USA

      Chris E. Adkins, Tori B. Terrell-Hall, Mohamed Afroz & Paul R. Lockman

    5. biOasis Technologies Inc., Vancouver, British Columbia, Canada

      Evelina Rubinchik, Tim Vitalis, Reinhard Gabathuler & Mei Mei Tian

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    1. Mohamed Ismail Nounou
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    Correspondence to Paul R. Lockman.

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    Mohamed Ismail Nounou and Chris E. Adkins are both considered as first authors.

    Mohamed Ismail Nounou and Chris E. Adkins contributed equally to this work.

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    Nounou, M.I., Adkins, C.E., Rubinchik, E. et al. Anti-cancer Antibody Trastuzumab-Melanotransferrin Conjugate (BT2111) for the Treatment of Metastatic HER2+ Breast Cancer Tumors in the Brain: an In-Vivo Study. Pharm Res 33, 2930–2942 (2016). https://doi.org/10.1007/s11095-016-2015-0

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