Tagworks’ technology enables the in vivo actuation of antibody drugs and imaging agents through systemic and selective chemical manipulation in vivo.
Antibody Drug Conjugates
Current antibody-drug conjugates (ADCs) target internalizing receptors on cancer cells leading to intracellular drug release via biological cleavage. Typically, only a subset of patients with solid tumors has sufficient expression of such a receptor, while there are sufficient suitable non-internalizing receptors and stroma targets.
Tagworks makes those targets amenable to ADC therapy by using a click reaction for selective antibody-drug cleavage in vivo instead of relying on intracellular biological activation mechanisms. In this two-step approach, tumor binding of the ADC and blood clearance of the unbound fraction is followed by systemic administration of an activator that reacts with the ADC linker in the extracellular space of the tumor, leading to drug release in the tumor microenvironment and subsequent uptake into surrounding cancer cells as well as tumor supporting stromal cells.
Click-cleavable ADCs expand the target scope and, in contrast to the inherent variability that can hamper endogenous mechanisms, enable universal and direct temporal control over drug release in the tumor microenvironment. This will allow a more homogenous drug delivery, thus potentially improving therapeutic efficacy in heterogeneous or poorly penetrated tumors.
Antibodies have long been recognized as selective and effective biopharmaceuticals and there is a widespread interest in imaging these drugs during drug development or as a companion diagnostic in the clinic. As antibodies circulate for a long time, there is a clear need to increase the target-nontarget ratio for better image quality and to reduce the radiation dose to the patient.
Tagworks’ technology improves the effectiveness of radioimmunoimaging by “pretargeting”, which centers on target binding of a tagged antibody and clearance from blood followed by binding of a small, fast-clearing, radiolabeled probe to the tag of the target-bound antibody in a second step. Optionally, remaining freely circulating antibody is cleared to the liver by injection of a clearing agent prior to probe injection. The resulting superior target-blood ratios enable effective imaging at markedly lower radiation doses to the animal or patient.
Clearing agents are designed to rapidly bind to the tag of the freely circulating antibody, after which the clearing agent-antibody combination is rapidly cleared from blood via the liver. In addition to increasing the target-blood ratios in the context of pretargeting this approach also enables increased ratios when imaging radiolabeled antibodies. In this approach, the radiolabeled and tagged antibody is allowed to circulate and bind its target, and subsequently unbound antibody is directed to the liver, improving image quality.
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