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).
Bibliographical noteFunding Information:
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).
- antibody trastuzumab-melanotransferrin conjugate (BT2111)
- blood brain barrier (BBB)
- brain metastases
- human melanotransferrin (hMTf)
- metastatic HER2+ breast cancer tumors
- trastuzumab (BTA)