The Application of Single Domain Antibodies in Biasing GPCR Signal Pathways – A Case Study with the Adenosine A2A Receptor – Year two

Single domain antibodies (sdAbs) represent a versatile class of heavy chain antibodies lacking a paired light chain and encoded by VHH germline genes typically expressed in camelids. KisoJi Biotech has developed a transgenic mouse line in which each mouse expresses multiple camelid VHH genes capable of specifically binding any antigen of interest. The small molecular weight of sdAbs (15 kDa) provides new opportunities to utilize these as specific ligands of G Protein-Coupled Receptors (GPCRs). One-third of current pharmaceuticals target GPCRs – the largest family of membrane proteins in the human genome and mediators of diverse biological processes through signal transduction. The adenosine A2A receptor (A2AR) is a prototypical class A GPCR and a target for the treatment of many diseases (1). Studies reveal A2ARs can stimulate multiple G protein pathways, with differing efficacies, depending on tissue type, ligand, and presence of other receptors. Our goal is to demonstrate the therapeutic utility of sdAbs to: i) achieve greater specificity and allosteric control of activation, ii) target specific functional states of the receptor, iii) achieve longer serum half-lives, and iv) improve tissue partitioning to obviate classical side-effects. This technology will then serve as a general platform for sdAbs to class A GPCRs.

Faculty Supervisor:

Scott Prosser

Student:

Partner:

KisoJi

Discipline:

Life Sciences

Sector:

Professional, scientific and technical services

University:

University of Toronto

Program: