This invention describes a general way to trigger the release of a bioactive small molecule from a targeting antibody. The key “trigger” is a fluorescent linker that is chemically disassembled upon irradiation with light in the near-IR range (~800 nm).
This linker technology is a dramatic step forward for the field. The molecules can be tracked using conventional fluorescence imaging technology, and with the application of a higher light dose, drug-release can be initiated in a targeted manner. In current clinical practice, a bulk tumor is often removed through a guided surgical approach with the tumor margins cleared by targeted irradiation. This technology promises fewer side-effects and the potential to pre-empt resistance issues by achieving higher, otherwise unattainable, drug doses. Compared to existing photodynamic therapy approaches, this technology relies on the activity of highly potent drug molecules, leading to dramatically improved potency.
To date, the inventors have demonstrated the ability to synthesize and use antibody conjugates that release the bioactive molecule duocarmycin. These ADCs display potent and highly selective activity in cellular assays. In vivo imaging has proven the ability to track and subsequently release the compounds with external irradiation from a continuous wave laser source. Significant antitumor efficacy has been observed following a single dose. Future studies are aimed at optimizing the physical properties of the conjugates and detailed in vivo efficacy and toxicology studies.
- To deliver a potent ADC payload with otherwise unattainable control through local irradiation
- Targeted cancer therapy
- In a basic research context, could be used to test the effect of timing, dose, and location of in vivo activity of payloads
- These studies are the first to illustrate in vivo drug delivery using antibody and light-based targeting
- Light in the near-IR range exhibits meaningful tissue penetration (up to several cms) and is non-toxic
- Enhanced potency compared to existing photodynamic therapies (PDT) that rely on the use of ROS as the major mediator of biological function
- In comparison to other ADCs, this approach should provide reduced off target release, while providing highly controlled delivery to irradiated areas of interest. These features should reduce toxicity, while providing improved efficacy for certain solid tumor applications (e.g. head and neck, bladder, and glioblastoma)
Nani RR, et al. In Vivo Activation of Duocarmycin-Antibody Conjugates by Near-Infrared Light. [PMID 28470051]
Nani RR, et al. Near-IR Light-Mediated Cleavage of Antibody-Drug Conjugates Using Cyanine Photocages. [PMID 26403799]
Gorka A, et al. A Near-IR Uncaging Strategy Based on Cyanine Photochemistry. [PMID 25211609]
- U.S. Provisional: U.S. Provisional Patent Application Number 62/373,666, Filed 11 Aug 2017
- U.S. Provisional: U.S. Provisional Patent Application Number