On June 6, 2024 Twist Bioscience Corporation (NASDAQ: TWST), a company enabling customers to succeed through its offering of high-quality synthetic DNA using its silicon platform, reported the publication of a study detailing the discovery of TB206-001, a first-in-class antibody targeting adenosine A2A receptor (A2AR), a promising molecular target that could enhance cancer immunotherapy (Press release, Twist Bioscience, JUN 6, 2024, View Source [SID1234644188]). The study titled, "Discovery of a potent, selective, and tumor-suppressing antibody antagonist of adenosine A2A receptor", was published in the journal PLOS ONE.
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A2AR is an emerging immune checkpoint that plays a role in the immunosuppression of the tumor microenvironment. It is part of an important class of therapeutic targets, called G protein-coupled receptors (GPCRs), which are found on most immune cells and highly expressed in certain cancers. Tumors commonly produce excess adenosine, which activates A2A receptors and suppresses immune cells. Blocking A2AR could alleviate the suppressive environment and restore tumor immunity. A2AR has been shown to play a role in various cancers including colorectal cancer, gastric cancer, lymph node metastasis, breast cancer and melanoma as well as in autoimmune diseases and Parkinson’s.
"The majority of current therapies in clinical trials targeting A2AR are small molecules, as it has been traditionally difficult to discover antibodies that block GPCRs; however, antibodies have greater affinity for target molecules, do not cross into the central nervous system and could be dosed less frequently," said Emily M. Leproust, Ph.D., CEO and co-founder of Twist Bioscience. "With the right partner to take it forward, TB206-001, our Twist-discovered first-in-class antibody antagonist of A2AR, could be developed as a powerful inhibitor to restore immune responses in immunosuppressive environments that allow cancer to grow."
In the study, the researchers immunized two different sets of animals with DNA encoding wildtype or mutant hA2AR (C144S, S334A, S338A) modified to minimize the impact of the receptor’s natural signaling on its expression. Once the animals generated antibodies to the receptor, the researchers built immune and synthetic single-chain variable fragment (scFvs) phage display libraries from the immune repertoire. The libraries were subsequently screened against detergent solubilized A2AR, and positive hits were reformatted into monoclonal antibodies for further testing. The result was TB206-001, which directly targets A2AR and activates immune cells. In preclinical studies, the antibody has shown high affinity and specific activity for A2AR over other adenosine receptors and shows tumor-suppressing activity in colon tumor-bearing HuCD34-NCG mice. Additional studies in animal models found that TB206-001 reduced tumor volume better than PD-1 inhibitors.
"There is still tremendous potential for immunotherapies either in combination with or in addition to those targeting PD-1 and CLTA-4," said Gregory Carven, Ph.D., one of the original inventors of Keytruda. "Using the ability to create large antibody libraries enabling discovery of novel and highly specific therapeutics, Twist has discovered an antibody that blocks A2AR, a promising checkpoint target and demonstrated its activity in preclinical models. The antibody could be further developed as a standalone therapy, bispecific or combination therapy to bring potential therapeutic benefit to patients."