Chemically Generated Bispecific Antibody-Drug Conjugates for Treating Triple-Negative Breast Cancer
Abstract
We will perform this proposed project to address one of the overarching challenges “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.” Triple-negative breast cancer (TNBC) has a poorer prognosis than other types of breast cancer due to its aggressive growth and early relapse. Chemotherapy along with surgery and/or radiation therapy is the major treatment option for patients with TNBC. While effective in some cases, patients with TNBC are frequently plagued with severe adverse effects derived from off-target cytotoxicity. Although targeted drug delivery is an attractive approach for reducing unwanted damage to normal cells, no targeted therapy has been approved for TNBC. The epidermal growth factor receptor (EGFR) is a cell-surface protein overexpressed in 50%-70% of TNBC cells. EGFR is a promising therapeutic target for TNBC treatment. While promising, 50%-90% patients experience adverse effects during anti-EGFR therapy, likely due to expression of EGFR in some normal cells. Thus, further improvement of the specificity and efficacy of anti-EGFR agents is critically needed to establish the anti-EGFR therapy as a safe and effective clinical option. Antibody-drug conjugates (ADCs) are emerging therapeutic agents for the treatment of cancers. We have developed novel chemical linkers that enable facile construction of ADCs targeting two distinct cancer-specific receptors. Based on this success, we hypothesize that such dual-targeting ADCs can overcome the specificity and efficacy issues in anti-EGFR therapy for TNBC. Here, we will prepare anti-EGFR ADCs incorporating a TNBC-specific small molecule using our technology and evaluate their toxicity profiles and treatment efficacy for TNBC. We envision that ADCs targeting both EGFR and another TNBC-specific receptor will exert higher TNBC specificity than conventional mono-targeting ADCs, leading to improved efficacy and reduced off-target cytotoxicity. Successful completion of this project will validate the new concept of “chemically constructed dual-targeting ADCs” as an innovative approach for treating TNBC and provide valuable additions to the current list of drug candidates to be tested in the future clinical studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910598
Entities
People
- Kyoji Tsuchikama
Organizations
- United States Army
- University of Texas Health Science Center at Houston