Breast cancer is the most diagnosed malignancy and the second cause of cancer death in women in the United States. The prognosis for breast cancer patients is particularly poor in those bearing tumors that overexpress the oncoprotein HER2/neu. Although, in general, antibodies used against cancer are of the IgG class, antibodies of the IgE class have several properties that make them advantageous for cancer therapy: 1) higher affinity of IgE for its Fc?Rs compared to IgG for its Fc?Rs, 2) expression of Fc?Rs by key cells responsible for antibody effector functions and antigen presentation, 3) low serum levels of endogenous IgE, resulting in less competition for FcR occupancy, and 4) unlike IgG, IgE does not have an inhibitory FcR. The present proposal seeks to develop a novel anti-HER2/neu antibody of the IgE class as a possible therapy of breast cancer. We hypothesize that the proposed anti-HER2/neu IgE will target HER2/neu expressing tumors and, in so doing, create a local IgE-targeted immediate hypersensitivity (anaphylactic) reaction resulting in acute inflammation in the tumor microenvironment and in rapid tumor destruction, with no escape of cancer cells. The dead cells will be taken up by antigen presenting cells (APC), such as dendritic cells, a process that can be enhanced when dead cancer cells are coated by IgE, resulting in an adaptive immune response not only against HER2/neu, but also against other tumor antigens due to epitope spreading. We also hypothesize that immunocomplexes composed of anti-HER2/neu IgE and soluble extracellular domain of HER2/neu (ECDHER2) will target APC, resulting in efficient antigen uptake and presentation with subsequent anti-tumor immune activation. We have already developed a totally human anti-HER2/neu IgE (C6MH3-B1 IgE) that does not compete with trastuzumab (Herceptin(R)) for its antigen-binding site. This novel IgE exhibits the expected biological properties and is capable of triggering immune activation and anti-tumor protection, while being well tolerated in relevant animal models. The goals of this proposal are: 1) Fill the gaps in the knowledge accrued from the previous studies, 2) open new lines of studies, and 3) create the basis to start moving the anti-HER2/neu IgE into the clinic. We have four independent specific aims:
Aim 1 : Define the interaction of anti-HER2/neu IgE and antigen in the context of effector cell functions and antigen presentation in vitro;
Aim 2 : Define the anti-tumor activity of anti-HER2/neu IgE in huFc?RI mice;
Aim 3 : Define the anti-tumor activity of anti-HER2/neu IgE in SCID mice;
and Aim 4 : Define the toxicity of anti-HER2/neu IgE in huFc?RI mice and cynomolgus monkeys. The present proposal has a mechanistic (basic science) component and a strong translational potential, which can contribute, potentially, to the cure of breast cancer and perhaps other HER2/neu overexpressing malignancies. The project is expected to open a new dimension in the nascent field of AllergoOncology, which aims to reveal the function of IgE-mediated immune responses against cancer and develop novel IgE-based cancer therapies such as the proposed therapeutic.

Public Health Relevance

Breast cancer is the most diagnosed malignancy and the second cause of cancer death in women in the United States. This project aims to develop a new therapeutic against a particularly aggressive type of breast cancer, tumors that overexpress HER2/neu. The proposed therapeutic is unique in that it is an antibody of the IgE class that aims to induce an allergic reaction in the tumor environment to fight off the tumor and teach the immune system that cancer cells are foreign enemies that should be destroyed.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01CA181115-01A1
Application #
8759266
Study Section
Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
Program Officer
Welch, Anthony R
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095