Click Chemistry-Triggered Activation of Antibody-Drug Conjugates
Abstract
Antibodies are large proteins that can bind to disease-specific targets on a cell. Antibody-drug conjugates (ADCs), also called "armed" antibodies, are a very new class of highly potent biopharmaceuticals that combine the disease-targeting ability of antibodies with the cancer-killing ability of highly cytotoxic drugs (toxins). The drug is bound to the antibody via a linker. After injection, ADCs selectively bind to a cancer-specific receptor on tumor cells. This receptor-ADC complex then enters the cell where the ADC linker is degraded and the drug is released, enabling the drug to kill the cell. In contrast to traditional chemotherapeutic agents, ADCs selectively attack cancer cells, so that healthy cells are less severely affected. This allows the safe use of drugs that have a 1000-fold increased potency compared with standard chemotherapy, leading to a boost in therapeutic efficacy. The two ADCs already on the market achieved impressive results: the recently approved Kadcyla against HER2-positive metastatic breast cancer affords doubling of the delay in disease progression compared with Herceptin. As current ADCs rely on intracellular cleavage of the linker between the antibody and the drug, the ADC has to bind to a cancer-specific receptor that is abundant on the cell membrane and very efficient in entering the cell after the ADC has bound. Unfortunately, only 20% of all breast cancers overexpress HER2, and there are no alternative receptors in breast cancer with the same potential. We aim to open up non-HER2-expressing breast cancer to ADC therapy, a new and highly potent treatment modality. This new class of ADCs will target non-internalizing receptors present in metastatic breast cancer tissue and can be chemically triggered to selectively release its potent cargo in the direct environment of the cancer cells. After the ADC has bound to an extracellular cancer target and free ADC has cleared from blood, a molecule (probe) is administered that reacts with the ADC linker via a click reaction to liberate and activate the drug. The extracellular released drug will penetrate and kill surrounding cancer cells in the direct environment. In addition, the extracellular release ensures that the drug also reaches and penetrates cancer cells that were not bound by an ADC. This is especially advantageous in poorly penetrable tumors (i.e., solid tumors) and is expected to afford an improved therapeutic outcome compared with current ADCs, as many more cancer cells will be reached and affected. This project aims to develop probes with a long circulation time in blood to maximize the on-tumor reaction time and yield and thereby the drug release. The highly potent drug monomethyl auristatin E (MMAE) will be conjugated to the anti-TAG72 antibody CC49 via the reactive linker, and the probe-induced drug release from this ADC and the therapeutic efficacy will be assessed in vitro and in tumor-bearing mice. The following Overarching Challenges will be addressed: (1) eliminate the mortality associated with metastatic breast cancer and (2) revolutionize treatment regimens by replacing drugs that have life-threatening toxicities with safe, effective interventions. Highly potent and selective therapies are imperative to improve the prognosis for women with metastatic breast cancer. Our proposed ADC approach expands the ADC scope to breast cancer targets such as TAG72, a specific and clinically validated pan-carcinoma marker that is present on 84% of breast cancers. It does not efficiently internalize and therefore cannot be used with the current ADC systems. Instead of the current 20%, 80+% of the breast cancers may become eligible for ADC therapy, including triple-negative breast cancer patients, who nowadays have very few options. We expect that click-chemistry-triggered ADC therapy will provide a large delay in disease progression and may furthermore have the potential to lead to complete cures due to the more hom
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510692
Entities
People
- Marc Robillard
Organizations
- Tagworks Pharmaceuticals (Netherlands)
- United States Army