Identification of novel breast cancer therapeutic antibodies
Gary Johanning , Ph.D. -
|Award Cycle:||2015 (Cycle 21)||Grant #: 21IB-0121||Award: $299,273|
|Detection, Prognosis and Treatment>Innovative Treatment Modalities: search for a cure|
Initial Award Abstract (2015)
Non-technical overview of the research topic and relevance to breast cancer: The FDA has approved 13 monoclonal antibodies (mAbs) for cancer therapy, but only 3 are for breast cancer. All 3 of these mAbs are against a single target, HER2, but only about 25% of breast cancers express HER2. Therefore, since only a limited number of therapeutic antibodies are available for breast cancer immunotherapy, we propose a rapid approach to discover novel antibodies obtained from breast cancer patients to treat these patients. We will use a combination of technologies to rapidly identify therapeutic fully human mAbs (humAbs). We hypothesize that this technology will enable us to not only discover new humAbs, but also to make sure that these humAbs can kill primary breast tumor cells, and can additionally kill specialized breast cancer cells called circulating tumor cells (CTCs) and cancer stem cells (CSCs). This screening approach can be accomplished rapidly and at a relatively low cost.
The question(s) or central hypotheses of the research: Our major objective is to produce fully human antibodies and test them for efficacy in killing breast cancer cells and making breast tumors shrink. To accomplish this objective, we will use an innovative technology called microengraving to identify these therapeutic humAbs. We hypothesize that this technology will enable us to discover human antibodies against a protein called HERV-K, which is found inside and on the surface of breast cancer cells. These studies will set the stage for finding many more fully human antibodies against other breast cancer targets. We will be able to screen thousands of antibodies in a short time at a relatively low cost. The questions we will ask are whether fully human antibodies can be produced rapidly, and whether the antibodies are effective in a) killing breast cancer cells, and b) blocking tumor formation in animal breast tumor models.
The general methodology: We have already identified a cohort of breast cancer patients with high serum levels of antibody against our HERV-K breast cancer target, and we have blood cells from these same patients frozen down. The blood cells from these breast cancer patients contain the human antibodies that will target and kill breast cancer cells. In fact, we already have found that B cells obtained from breast cancer patients contain antibodies that can kill breast cancer cells. We will work on the patients who have both blood and tissues samples available to see if the B cells from these patients can kill the patientsí own breast cancer cells; if so this would be a way to personalize these patientsí treatment for breast cancer. Cells from the tumor biopsies (or CTCs or CSCs) will be grown and will be used as the cells targeted by antibodies that bind the HERV-K on the cell surface. These humAbs are the ones that will kill the tumor cells. Our goal is to rapidly identify even small numbers of humAbs by extensive screening using the microengraving technology. Single B cells that produce killing humAbs will be retrieved using our brand new CellCollector automated micromanipulator. Once we produce candidate humAbs, we will test them for effectiveness in killing breast cancer cells grown in dishes, and for effectiveness in blocking human breast tumor growth in mouse models of breast cancer.
Innovative elements of the project: We will use an innovative microengraving technology to discover many more fully human antibodies against breast cancer, with a high-throughput and low cost. These antibodies have several advantages: since they are 100% human, they are less toxic to patients than antibodies containing some mouse parts, which are commonly used in the clinic; the humAbs do not need to be administered as frequently since they are fully human, and they can be administered for a longer time period since they have lower toxicity; and they would have greater ability to kill breast cancer cells. There is a potential for discovery of many more breast cancer human antibodies if our IDEA is successful. Finally, these humAbs will be produced relatively quickly.therapy has been shown effective.