ECTACS: Endothelial Cell-Targeted Amatoxin Conjugates for Improved Therapy of Breast Cancer
Abstract
The research seeks to revolutionize breast cancer treatment regimens using trastuzumab by replacing them with ones that are more effective and less toxic. To do this, we will develop a novel caveolae-targeting bispecific antibody that links trastuzumab to hAnnA1, the first antibody to be actively transported across the vascular endothelial barrier into solid tumors. Patients with Human Epidermal growth factor Receptor 2-positive (HER2+) breast cancers, especially those with recurring or drug-resistant disease, may be among those most likely to benefit from our research. Trastuzumab (Herceptin®) is the first Food and Drug Administration-approved therapeutic targeting HER2+ cancers. It is used for adjuvant treatment of early-stage HER2+ breast cancer as well as first-line treatment of HER2+ metastatic breast cancer. HER2(+) is observed in 20%-30% of invasive breast carcinomas. Within HER2+ breast cancer patients, high proportions do not respond to trastuzumab: there are 20%-50% non-responders in adjuvant setting and 70% non-responders as monotherapy. These are “primarily” or “inherently” resistant to the drug. Most (70%) initial responders eventually progress to metastatic disease within a year, presumably some due to acquired resistance (secondary resistance). Our cancer therapy will apply to most HER2+ breast cancer patients. Existing drugs for HER2+ breast cancer rely on trastuzumab getting in the blood and traveling to the tumor, and then “leaking” inside the breast tumors. This mode of delivery via “leaking” is inefficient. Most of a typical trastuzumab dose fails to concentrate inside the tumor because the blood vessels do not allow the drug to cross from blood into the tumors. Only a very small amount of drug actually reaches the inside of tumors (<0.01%) where the drugs can kill the cancer. Hence, ever-increasing doses must be administered to achieve efficacy. Also, decrease in functional HER2 copies on trastuzumab-resistant cancer cells reduces efficacy and therapeutic index. As a result, new, radically different therapies are urgently needed to overcome these significant biological barriers that inhibit in vivo delivery and limit therapeutic efficacy of trastuzumab. This research proposal is aimed to explore and exploit our novel caveolae delivery system to actively, rapidly, and specifically pump targeted trastuzumab directly into breast tumors. We propose to link the caveolae-targeting antibody hAnnA1 to trastuzumab in the form of a bispecific antibody. This approach will increase trastuzumab delivery to tumors for enhanced efficacy and potency. This bispecific antibody may lead to tumor eradication at low dosages and thus limit off-target toxicity. It would represent a novel class of therapeutics that may improve responsiveness to trastuzumab in a broader range of patients with different copy numbers of a functional HER2 receptor. The potential clinical applications are tremendous as this unique bispecific drug platform could provide a means to significantly reduce effective therapeutic doses of trastuzumab and alleviate unwanted side effects on organs like the heart. Development and production of T-hAnnA1, a bispecific antibody that targets trastuzumab to tumor caveolae, is proposed for the first half of the funding period. The second half of the program will include testing and validating T-hAnnA1 in relevant animal models. If successful, our strategy will have a profound and significant impact on how we currently treat primary breast cancer and breast cancer that has spread to other parts of the body that are HER2+. Our system could potentiate many other anti-cancer drugs. Ultimately, our goal is to supplement the growing arsenal of therapeutic weaponry by providing a precision-guided drug delivery platform for use in the war on cancer. If we are correct, and our pumping system and our antibody work in humans properly, the proposed studies could be a major step towards a cu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910705
Entities
People
- Jan Schnitzer
Organizations
- Proteogenomics Research Institute for Systems Medicine
- United States Army