Click-Cleavable ADCs targeting TAG72
- The tumor-associated glycoprotein 72 (TAG72) is a non-internalizing target widely expressed in a range of epithelial-derived human adenocarcinomas such as breast, colorectal, stomach, lung, pancreatic, prostate and ovarian cancers.
- Tagworks is developing click-cleavable anti-TAG72 ADCs based on several antibody fragment types, armed with the potent anti-mitotic agent MMAE.
- The small size and fast clearance from circulation and normal tissues enables effective ADC tumor uptake combined with reduced off-target payload release and toxicity.
- The fast ADC clearance allows administration of the activator 1-3 days later, affording rapid release of MMAE in the tumor microenvironment and diffusion into surrounding tumor cells, maximizing the bystander effect.
- A diabody-based anti-TAG72 MMAE ADC showed potent anti-tumor therapy in mice bearing colorectal and ovarian cancer xenografts without detectable toxicity. In comparison, an analogous ADC containing the enzymatically-cleavable valine-citrulline linker used in Adcetris was not effective in these models.
In vivo click chemistry for companion diagnostics
- Tagworks partners with biopharma companies on the use of the click pretargeting technology and /or the click clearing technology for the imaging of antibodies in their development pipelines.
- In our click pretargeting approach the antibody is functionalized with a small tag (trans-cyclooctene), typically through lysine or cysteine conjugation, and administered in vivo. After accumulation at the target site and elimination from blood and non-target tissues, its biodistribution is determined by injecting a small radiolabeled probe (tetrazine), which binds rapidly and selectively to the tag at the target site or is otherwise eliminated via the kidney.
- In our click clearing approach the antibody is functionalized with the trans-cyclooctene tag and a chelator for radiolabeling. After target binding of the antibody (e.g. to an amyloid plaque in the brain), a tetrazine-functionalized clearing agent is administered that removes residual radioactivity from the blood stream boosting the target-blood ratio.
- Both these approaches produce excellent image contrast in short times (few hours instead of several days) allowing the use of short-lived radionuclides (e.g. F-18, Ga-68, etc.) with low radiation doses to the patient or animal and improved logistics.
Example of SPECT image with combined tumor pretargeting and clearing agent approaches: mouse bearing a subcutaneous colon carcinoma xenograft (LS174T) pretreated with a tagged mAb (CC49) followed by injection of clearing agent (48h post-mAb injection) and 111In-labeled probe. The SPECT/CT imaged shows high radioactivity uptake in tumor and extremely low background in non-target tissues.