Targeting Metastatic Breast Cancer with Human Antibodies

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Today's advancing technologies can detect very early breast tumors. However, current prognostic criteria for breast cancer do not accurately indicate how aggressive a tumor is, whether it has already begun to spread, and which treatment options should be chosen to achieve the best possible outcome in each individual case. Breast cancer metastasis to the lungs, liver, bone and brain involves tumor cell dissemination via the blood stream, and studies, in vitro and in vivo, showed that a metastatic subset of human breast cancer cells expresses an adhesion receptor, the integrin alphavbeta3, in a constitutively activated functional form. This receptor enables the cells to bind platelets and arrest during blood flow, as found in the circulation, and it also supports invasive tumor cell migration and survival. The long-term objective is to target functional markers of metastatic breast cancer cells, such as the activated integrin ava3, for early detection, prevention and inhibition of metastatic disease. We used antibody phage display technology and a subtractive panning strategy on poorly versus highly metastatic variants of a human breast cancer cell model to isolate human single chain Fv (scFv) antibodies that identify metastatic breast cancer cells by targeting the activated conformation of integrin ava3. These antibodies have ligand mimetic properties and inhibitory functions that interfere with lung colonization by human breast cancer cells in a mouse model, and they inhibit existing metastatic disease. The goal of this work is to test the hypothesis that human scFvs against activated ava3, and other novel markers of metastatic breast cancer cells can be optimized to 1. report metastatic disease, 2. detect cells with a metastatic propensity, and 3. inhibit breast cancer metastasis. The scFvs will be modified by chemical and molecular engineering to enhance their activity for each intended application. Imaging systems will use tagged scFv antibodies to track metastatic cells in the circulation and to identify micro-metastatic lesions. Novel immunoconjugates containing small, highly toxic compounds will be tested for their effects on metastatic breast cancer. If successful, this work will contribute to an improvement of current anti-cancer treatment.