TY - JOUR
T1 - Anti-cancer Antibody Trastuzumab-Melanotransferrin Conjugate (BT2111) for the Treatment of Metastatic HER2+ Breast Cancer Tumors in the Brain
T2 - an In-Vivo Study
AU - Nounou, Mohamed Ismail
AU - Adkins, Chris E.
AU - Rubinchik, Evelina
AU - Terrell-Hall, Tori B.
AU - Afroz, Mohamed
AU - Vitalis, Tim
AU - Gabathuler, Reinhard
AU - Tian, Mei Mei
AU - Lockman, Paul R.
N1 - Publisher Copyright:
© 2016, Springer Science+Business Media New York.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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).
AB - 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).
KW - antibody trastuzumab-melanotransferrin conjugate (BT2111)
KW - blood brain barrier (BBB)
KW - brain metastases
KW - human melanotransferrin (hMTf)
KW - metastatic HER2+ breast cancer tumors
KW - trastuzumab (BTA)
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U2 - 10.1007/s11095-016-2015-0
DO - 10.1007/s11095-016-2015-0
M3 - Article
C2 - 27528392
AN - SCOPUS:84982163200
SN - 0724-8741
VL - 33
SP - 2930
EP - 2942
JO - Pharmaceutical research
JF - Pharmaceutical research
IS - 12
ER -