Spontaneous breast and other cancers are often complex and heterogeneous. A current driving theme in the field of cancer biology is to refine our methods to characterize patient tumors on a molecular level such that therapies can be tailored to each individual patient. We have developed a method to utilize the patient's own immune response to isolate antibodies that they make against their cancer proteins. In the laboratory we synthesize these antibodies and identify novel cancer proteins targeted by these antibodies. The main goal of this application is to implement a platform-based method to isolate and identify tumor-specific antibodies and their cancer-specific antigens. This platform technology has the potential to yield hundreds of antibodies that can be used to target individual cancers that express the antigen recognized by these antibodies. It is the intention of these investigators to use these reagents to expand our understanding of breast cancer biology, detection of cancer specific biomarkers and as novel therapeutic treatments. These single domain antibodies are infinitely renewable and hold great promise as tools for population based biomarker screening and individualized patient-specific targeted therapy for advanced and metastatic disease.
The specific aims of this application will focus on four specific goals:
Specific Aim 1 - Perform throughput platform screening of at least 40 breast cancer cases representing up to 65 total libraries and identification of an estimated 1000-1500 novel VH antibodies.
Specific Aim 2 - Identify the cognate antigens for 200-400 antigen driven VH single domain antibodies identified in Aim 1 based upon clonal expansion and somatic hypermutation scores.
Specific Aim 3 - Validate identified antigens and their presentation in human breast cancer using multiplex large scale arrays.
Specific Aim 4 - Assemble multiplex protein arrays of recombinant soluble domain antibodies and matching arrays of their cognate antigens for use in cancer diagnostic, screening and clinical targeting applications.
Discovery Platform for Cancer Antigens applies a unique biochemistry and molecular biology technology that we have developed that recovers antibodies from patients and identifies cancer proteins that the immune system has targeted as """"""""abnormal"""""""". The incorporation of this platform will facilitate the development of reagents which will be useful in understanding cancer biology, detection reagents for diagnostic biomarker screening, as well as long-term potential for individualized therapeutics based upon the expression of these """"""""abnormal"""""""" proteins in any patient. The platform will be applied primarily to breast cancer but holds great promise for applications to most other cancers. Finally, these reagents will be made available to the broad cancer research community to rapidly define their utility and application in multiple diagnostic and clinical therapeutic approaches.
|Devarakonda, Charan V; Kita, Daniel; Phoenix, Kathryn N et al. (2015) Patient-derived heavy chain antibody targets cell surface HSP90 on breast tumors. BMC Cancer 15:614|
|Rodriguez-Pinto, Daniel; Sparkowski, Jason; Keough, Martin P et al. (2009) Identification of novel tumor antigens with patient-derived immune-selected antibodies. Cancer Immunol Immunother 58:221-34|