Mohamed Ismail Nounou1,2,3, Chris E Adkins1,4, Evelina Rubinchik5, Tori B Terrell-Hall1,4, Mohamed Afroz1,4, Tim Vitalis5, Reinhard Gabathuler5, Mei Mei Tian5, Paul R Lockman6. 1. School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, USA. 2. Department of Pharmaceutics, School of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. 3. Department of Pharmaceutical Sciences, Appalachian College of Pharmacy, Oakwood, Virginia, 24631, USA. 4. School of Pharmacy, West Virginia University Health Sciences Center, Morgantown, West Virginia, USA. 5. biOasis Technologies Inc., Vancouver, British Columbia, Canada. 6. School of Pharmacy, West Virginia University Health Sciences Center, Morgantown, West Virginia, USA. prlockman@hsc.wvu.edu.
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).
PURPOSE: The ability of humanmelanotransferrin (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 humanHER2+ 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 humanHER2+ 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).
Entities:
Keywords:
antibody trastuzumab-melanotransferrin conjugate (BT2111); blood brain barrier (BBB); brain metastases; human melanotransferrin (hMTf); metastatic HER2+ breast cancer tumors; trastuzumab (BTA)
Authors: Gideon M Blumenthal; Nancy S Scher; Patricia Cortazar; Somesh Chattopadhyay; Shenghui Tang; Pengfei Song; Qi Liu; Kimberly Ringgold; Anne M Pilaro; Amy Tilley; Kathryn E King; Laurie Graham; Barbara L Rellahan; Wendy C Weinberg; Bo Chi; Colleen Thomas; Patricia Hughes; Amna Ibrahim; Robert Justice; Richard Pazdur Journal: Clin Cancer Res Date: 2013-06-25 Impact factor: 12.531
Authors: Erin M Olson; Julie S Najita; Jessica Sohl; Amal Arnaout; Harold J Burstein; Eric P Winer; Nancy U Lin Journal: Breast Date: 2013-01-23 Impact factor: 4.380
Authors: Iku Moroo; Maki Ujiie; Brandie L Walker; Jacqueline W C Tiong; Timothy Z Vitalis; Delara Karkan; Reinhard Gabathuler; Alexander R Moise; Wilfred A Jefferies Journal: Microcirculation Date: 2003-12 Impact factor: 2.628
Authors: George Thom; Mei-Mei Tian; Jon P Hatcher; Natalia Rodrigo; Matthew Burrell; Ian Gurrell; Timothy Z Vitalis; Thomas Abraham; Wilfred A Jefferies; Carl I Webster; Reinhard Gabathuler Journal: J Cereb Blood Flow Metab Date: 2018-05-30 Impact factor: 6.200
Authors: Jennifer Hazel Elizabeth Baker; Alastair Hugh Kyle; Stefan Alexander Reinsberg; Firas Moosvi; Haley Margaret Patrick; Jordan Cran; Katayoun Saatchi; Urs Häfeli; Andrew Ivor Minchinton Journal: Clin Exp Metastasis Date: 2018-09-08 Impact factor: 5.150
Authors: Chaahat S B Singh; Brett A Eyford; Thomas Abraham; Lonna Munro; Kyung Bok Choi; Mark Okon; Timothy Z Vitalis; Reinhard Gabathuler; Chieh-Ju Lu; Cheryl G Pfeifer; Mei Mei Tian; Wilfred A Jefferies Journal: Front Neurosci Date: 2021-06-02 Impact factor: 4.677