DEVELOPMENT OF BISPECIFIC T CELL ENGAGERS TARGETING CARBONIC ANHYDRASE 9 FOR THE IMMUNE THERAPY OF CLEAR CELL RENAL CELL CARCINOMA

Advanced clear cell renal cell carcinoma (ccRCC) is responsible for nearly 70% of kidney cancers and 10,000 yearly deaths in the Unites States. While immunotherapies have demonstrated potential, poor chances of long-term survival remain for advanced cases. Yet to reach patients are bispecific T cell engaging antibodies (BTEs) that target T cell cytotoxicity to tumors by simultaneously binding T cell and cancer antigens, for which exist multiple design formats. However, there are limited comparative characterizations among formats for the optimal selection and design of new therapies. Here, we sought to develop BTEs to treat advanced ccRCC by targeting the antigen, carbonic anhydrase 9 (CA9), while characterizing the clinically relevant Persistent BTE (PBTE) format, advancing its design concept, and testing in vivo delivery through synthetic DNA (dBTEs). We show that, compared to a prototypical BTE, PBTE formatting weakens synapses by 3-fold through a novel application of avidity sensors, while reducing potency by 33-fold against some RCC cells and dPBTE efficacy by nearly 2-fold in mouse models. However, providing 2:1 CA9 bivalency with a novel Persistent Multivalent T Cell Engager (PMTE) format restores avidity, recovers potency by up to 41-fold, and doubles tumor distribution, to deliver greater dPMTE efficacy by up to 20-fold higher tumor control. This study demonstrates the importance of format characterization and design optimization prior to the clinical development of BTEs. This study also supports the CA9-targeted dPMTE as a promising new immunotherapy against advanced ccRCC, alongside its format to repurpose for other cancers.

Author dc:creator

• O'Connell, Ryan

Advisor dc:contributor.advisor

• Weiner, Ph.D., David, B

• Pharmacology, Toxicology and Environmental Health
• Biology
• Engineering

Language dc:language.iso

en

Repository record dc:identifier.uri

https://repository.upenn.edu/handle/20.500.14332/60854

OAI identifier oai:identifier

oai:repository.upenn.edu:20.500.14332/60854